The histidine phosphatase LHPP: an emerging player in cancer

ABSTRACT

Cancers continue to have high incidence and mortality rates worldwide. Therefore, cancer control remains the main public health goal. Growing research evidence suggests that phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) plays an important role in inhibiting tumor cell progression. It has been reported in the literature that LHPP is expressed at low levels in tumor tissues and cells and that patients with low LHPP expression have a poorer prognosis. Functional studies have shown that LHPP can inhibit tumor cell proliferation, metastasis, and apoptosis by affecting different target genes. In addition, researchers have used iDPP nanoparticles to deliver LHPP plasmids to treat tumors, demonstrating the great potential of LHPP plasmids for cancer therapy. In our review, we highlight the biological functions and important downstream target genes of LHPP in tumors, providing a theoretical basis for the treatment of human cancers. Although not thoroughly studied in terms of tumor mechanisms, LHPP still represents a promising and effective anticancer drug target.

KEYWORDS:

• LHPP
• tumor
• target genes
• mechanism

1. Background

Phosphorylation of proteins is regulated by protein kinases and phosphatases and is involved in various functions, such as cell growth and metabolism. Protein phosphorylation occurs on amino acid residues such as serine (Ser), threonine (Thr), tyrosine (Tyr), aspartic acid, glutamic acid, cysteine, histidine, lysine and arginine. Histidine phosphorylase was first reported by Boyer in 1962. Researchers first identified this enzyme as succinyl coenzyme A synthase, a key enzyme of the tricarboxylic acid cycle. Phosphorylation of the imidazole nitrogen atom of histidine forms a high-energy amino-phosphate bond, while phosphorylation of Ser, Thr, and Tyr forms a more stable phosphate ester bond [1]. Due to its chemical instability, histidine phosphorylation has been less studied in the last half century. In recent years, with the development of biological techniques, histidine phosphorylation has been found to be involved in cell signaling processes as a reversible regulatory modification in cells. In tumor cells, histidine kinases and phosphatases participate in cancer development by regulating the phosphorylation of histidine-containing proteins.

1.1 Histidine kinases

The histone kinases mainly include histone H4 histidine kinase (HHK) and nucleoside diphosphate kinase (NDPK). Chen et al. first identified HHK in the nuclei of regenerating rat hepatocytes. Increased HHK activity was associated with liver progenitor cell proliferation and differentiation, suggesting that HHK may be involved in cancer development and progression. HHK activity was significantly higher in hepatocellular carcinoma tissues than in paraneoplastic and normal liver tissues. The expression pattern of HHK was similar to that of tumor developmental markers, such as methemoglobin and pyruvate kinase isoenzymes [2].

NDPK is a nucleotide-metabolizing enzyme encoded by NME genes (involved in neoplasm metastasis), of which NME1 has the highest sequence homology with NME2 and is therefore the most widely studied [3]. Overexpression of NME1 in melanoma, breast cancer and ovarian cancer was shown to inhibit tumor metastasis and increase the overall survival of patients [4]. However, NME1 promotes tumor metastasis in hepatocellular carcinoma, acute myeloid leukemia and neuroblastoma [5]. The dual role of NME1 in tumors may be related to the differences in various biochemical characteristics of NME1 in different tissues, such as NDPK activity and histidine protein kinase activity. NME2 can also function as a metastasis regulator to regulate the occurrence and development of tumors in different cellular environments. NME2 mediates the phosphorylation of Ser5 at the c-terminus of RNA polymerase II by interacting with RNA polymerase II and RNA polymerase II-related protein 2 and promotes the transcription of anti-apoptosis-related genes, thereby inhibiting tumor growth in vivo [6].

1.2 Histidine phosphatases

The known histidine phosphatases are phosphohistidine phosphatase 1 (PHPT1), phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP), and phosphoglycerate mutase 5 (PGAM5) [7]. Histidine phosphatases play a critical role in cell signaling, and their expression and dysfunction play an important role in tumor progression. PHPT1 was the first protein histidine phosphatase to be discovered in vertebrates and humans, and it dephosphorylates the β-subunit of ATP-citrate lyase and G proteins in vitro [^8–11]. Studies on the mechanisms associated with tumor progression revealed that higher PHPT1 expression was associated with enhanced invasion of tumor cells; in addition, both in vivo and in vitro studies revealed the important role of PHPT1 in regulating lung cancer cell migration [12,13]. In renal clear cell carcinoma and hepatocellular carcinoma, PHPT1 plays a role in tumorigenesis and development by regulating the proliferation and apoptosis of tumor cells [14,15]. As a cytosolic Ser/Thr phosphatase, PGAM5 is involved in several functions that affect mitochondrial homeostasis. Ma et al. showed that PGAM5 interacts with the BCL-xL and FUNDC1 proteins to modify the mediated molecular switch that regulates mitochondrial autophagy and apoptosis to promote tumor progression [16,17]. In colon cancer cells and cervical cancer cells, PGAM5 induces cell death by regulating mitochondrial fission and necrosis [18]. In addition, some studies have reported that elevated PGAM5 expression leads to a poorer prognosis for patients. Knockdown of PGAM5 inhibits tumor cell proliferation and enhances the chemotherapy sensitivity of tumor cells [19]. In this article, we focus on the newly discovered histidine phosphatase LHPP and its mechanism as a tumor suppressor gene in inhibiting cancer cell progression.

2. Introduction to LHPP

The LHPP gene encodes an enzyme called lysine phosphate histidine inorganic pyrophosphatase (LHPP); LHPP was first isolated from porcine brain tissue, is expressed at high levels in the brain, and is a member of the halogen dehydrogenase structural domain (HDHD) gene family [20]. LHPP is also a novel inorganic pyrophosphatase that is closely associated with cell growth and polarization [21]. LHPP polymorphisms are related to thyroid hormone (TH) levels and are believed to mediate functional modification in patients with major depressive disorder (MDD) [22]. Cui et al. showed that a single nucleotide polymorphism in the LHPP gene (rs35936514) was associated with MDD in a genome-wide association study [23]. LHPP gene is located on q26.13 of chromosome 10 [24]. In addition, it was revealed that LHPP is mainly located in the nucleus and cytoplasm [25,26]. In 2018, researchers demonstrated that LHPP is a protein histidine phosphatase and tumor suppressor and that it acts extensively on N3 phosphorylated proteins [27]. In our review, we concentrate on the features of LHPP in important cancers and its regulatory molecules. In addition, we explored the potential application value of LHPP as a therapeutic target.

3. The function of LHPP in tumors

Because LHPP has been shown to be a tumor suppressor, it has become a highly researched topic in the field of tumor research, and many experiments have demonstrated that LHPP plays a key role in various tumor progression processes, including proliferation, metastasis, and apoptosis [26^,28–34]. LHPP is mainly expressed in brain and thyroid tissue, and its expression in different tissues is shown in Figure S1. In addition, it was found in the tumor immune estimation resource (TIMER) data that LHPP expression was significantly lower in BLCA (bladder urothelial carcinoma), CHOL (cholangiocarcinoma), COAD (colon adenocarcinoma), KICH (kidney chromophobe), KIRC (kidney renal clear cell carcinoma), PRAD (prostate adenocarcinoma), READ (rectum adenocarcinoma), and STAD (stomach adenocarcinoma) compared with normal tissues. However, LHPP expression was significantly higher in LUAD (lung adenocarcinoma) compared with normal tissues (Figure 1). Further studies revealed that LHPP overexpression attenuated the proliferation and metastasis of human hepatocellular carcinoma (HCC) cells by inhibiting the expression of Cyclin B1 (CCNB1), Pyruvate Kinase M2 (PKM2), Matrix metallo proteinase 7/9 (MMP7/9) [31]. In addition, in colorectal cancer (CRC), LHPP inhibited the growth and proliferation and promoted the apoptosis of CRC cells by affecting the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and cell cycle signaling pathways [35]. All these results suggest that LHPP plays an important role in inhibiting tumor progression. This article mainly summarizes the existing evidence on the aberrant expression, molecular mechanisms and clinical relevance of LHPP.

Figure 1. Human LHPP expression levels in different tumor types from The Cancer Genome Atlas database were determined by TIMER (https://cistrome.shinyapps.io/timer/), and the differential expression was evaluated by Wilcoxon test. TPM:Transcripts Per Million. Red: Tumor, Blue: Normal. (*P < 0.05, **P < 0.01, ***P < 0.001).

–: Not reported in literature

–: Not reported in literature

3.1 LHPP and liver cancer

Liver cancer has a poor prognosis due to its high proliferation and metastatic capacity [36]. Therefore, it is crucial to understand the potential mechanisms of proliferation and metastasis in hepatocellular carcinoma (HCC) for treatment. Recent studies have shown that nearly half of patients with HCC show abnormal PI3K-AKT-mTOR signaling, mainly including loss of the tumor suppressors Phosphatase and tensin homolog (PTEN), Tuberous Sclerosis 1/2 (TSC1/2). Hindupur et al. successfully constructed a mouse HCC model by knocking out both the PTEN and TSC1 genes [37,38]. Decreased LHPP expression was correlated with tumor progression but not with mTOR activity. The researchers also found that overexpression of LHPP in CB1 and SNU449 cells inhibited cell proliferation and significantly reduced hepatosphere formation in CB1 cells. A reduction in LHPP expression in human HCC leads to enhanced histidine phosphorylation and reduced survival. LHPP inactivation was shown to be a key factor for tumorigenesis in HCC [27]. Liao et al. found that LHPP was decreased in HCC patients. The increased expression of LHPP may be related to the overall survival and disease-free survival of HCC. In addition, LHPP expression was reduced in HCC cell lines compared to normal cell lines. Further studies showed that LHPP overexpression attenuated the proliferation and metastasis of human HCC cells by inhibiting the expression of CCNB1, PKM2, MMP7, and MMP9 [31]. Another study related to HCC showed that miR-765 levels in HCC tissues and miR-765 levels in HCC serum were significantly negatively correlated with LHPP in HCC tissues. Studies of hepatocellular carcinoma cell lines revealed that miR-765 directly targets and binds LHPP at the 3’ untranslated region (3ʹUTR) sequence. MiR-765 overexpression promoted epithelial−mesenchymal transition (EMT) and proliferation through downregulation of LHPP expression and inhibited apoptosis in HepG2 cells [39]. Similar studies have also shown that miR-363-5p and miR-765 bind directly to LHPP to play a targeted regulatory role [40].

Another study by Wang et al. demonstrated the role of LHPP in intrahepatic cholangiocarcinoma (ICC). The investigators found that LHPP was downregulated in tumor tissue and that low levels of LHPP predicted poor survival. Low LHPP expression predicts better overall survival in HCC patients. In vivo and in vitro experiments found that LHPP inhibited ICC cell growth, invasion, and EMT. Further mechanistic studies revealed that LHPP inactivated the transforming growth factor-β (TGFβ) signaling pathway and that interference with LHPP led to enhanced TGFβ expression and phosphorylation of smad2/3. In addition, restoration of normal pathway function reversed the biological function of LHPP [33].

This evidence suggests that aberrant expression of LHPP is related to the advancement of liver cancer. LHPP may be a potential oncogene in liver cancer. These results provide new insights into the mechanisms involved in the development of liver cancer.

3.2 LHPP and CRC

Globally, CRC is one of the most common malignancies in humans and the leading cause of tumor-related deaths [41,42]. Therefore, it is crucial to find new therapeutic targets for CRC. The PI3K/AKT signaling pathway plays an extremely important role in cellular activities, including cell proliferation, migration, autophagy, and other functions. Moreover, an increasing number of studies have shown that PI3K/AKT inhibitors are promising in the treatment of CRC [43,44]. IIn another study, similar results also showed that the LHPP protein inhibits CRC cell growth by suppressing the PI3K/AKT signaling pathway and that overexpression of the LHPP protein suppresses the expression of the EGFR, cyclin-D1, and NF-κB proteins in HCT-116 cells [45]. Aberrant expression of tumor suppressor genes enhances the expression of antiapoptotic proteins and attenuates the expression of proapoptotic proteins; this mechanism underlies colorectal carcinogenesis [46,47]. Hu et al. determined that purpurin strongly interacts with LHPP by binding to it through hydrophobic and hydrophilic bonds. Furthermore, purpurin promoted the expression of the apoptotic genes Bax, caspase-9, and caspase-3 in HCT-116 cells by inducing the expression of LHPP [45]. Hou et al. showed that LHPP expression was reduced in CRC tissues compared to normal colorectal tissues and that increased expression of LHPP may be related to tumor size, TNM stage and lymphatic metastasis of CRC. However, bioinformatics studies found that LHPP was not associated with patient prognosis. These differences are likely due to the limited sample size, slightly different genetic mutations in different countries, and differences in surgeon surgical skills, which play have a crucial effect on the outcome of CRC patients. Mechanistic studies in vivo and in vitro have shown that LHPP can inhibit the growth and proliferation of CRC cells and promote their apoptosis through the PI3K/AKT and cell cycle signaling pathways [35]. Mechanistic studies have shown that LHPP inhibits CRC cell proliferation and metastasis through the TGF-β/Smad signaling pathway [48]. Therefore, LHPP may suppress CRC progression. This idea suggests that low expression of LHPP leads to poor prognostic survival of CRC and that elevated expression of LHPP inhibits proliferation and metastasis and promotes apoptosis of CRC cells.

3.3 LHPP and PCa

PCa, one of the most common types of cancer in men, still has a poor survival rate and prognosis, despite advances in medical technology that have further improved its diagnosis and treatment [^49–51]. Therefore, to improve the diagnosis and treatment of PCa, we urgently need to find new potential therapeutic targets. YTHDF2, a, important cytoplasmic m6A reader, degrades N⁶-methyladenosine (m6A)-modified mRNA by binding to m6A sites and promotes tumor progression in multiple cancers [^52–55]. Li et al. found that YTHDF2 enhances AKT phosphorylation in PCa by targeting the tumor suppressor LHPP for degradation. The researchers also found that LHPP is a novel tumor suppressor that inhibits the proliferation and metastasis of PCa cells by inhibiting the phosphorylation of vehicle AKT. Investigators have shown through in vitro and in vivo studies that LHPP can mediate mRNA degradation in an m6A-dependent manner via upstream YTHDF2 to regulate PCa tumor progression [56]. Lin et al. found that LHPP expression was downregulated in PCa samples compared to normal prostate samples. Interestingly, LHPP expression was downregulated in N1 grade PCa patients compared to N0 grade patients. In vivo studies revealed that silencing LHPP inhibited the proliferation and metastatic capacity of 22Rv1 and PC-3 cells via E-cadherin and vimentin. These data suggest that LHPP inhibits EMT progression in PCa. Further study of the mechanism showed that upregulation of the circular RNA DDX17 promoted LHPP mRNA and protein expression, and miR-346 could bind directly to the 3ʹUTR of LHPP. These results suggest that circDDX17 can promote LHPP expression by binding miR-346 [57]. The experimental results of the abovementioned studies suggest that LHPP can regulate the progression of PCa and provide a theoretical basis for LHPP as a potential therapeutic target in PCa.

3.4 LHPP and glioblastoma

Glioblastoma (GBM) is one of the most common and fatal malignancies in the nervous system and has some of the highest rates of morbidity and mortality. Despite advances in modern medical technology, the highly proliferative and aggressive cellular characteristics of GBM lead to poor treatment outcomes and prognosis [58,59]. Therefore, we need to further explore the specific progression of GBM tumors and develop new therapeutic targets. Wnt/β-catenin signaling is widely involved in the progression of many cancers, including GBM [60,61]. It has been reported that LHPP expression is downregulated in GBM. In addition, LHPP inhibits the proliferation and metastasis of GBM through the Akt and Wnt/β-catenin signaling pathways, and reactivation of Wnt/β-catenin signaling reverses the tumor suppressive effect of LHPP [29]. Another study also found that LHPP was abnormally reduced in GBM and that patients with lower expression of LHPP had a poorer prognosis. Mechanistic studies have shown that LHPP inhibits glycolysis in tumor cells by inducing ubiquitin-mediated PKM2 degradation. In addition, increasing PKM2 expression effectively reversed the growth inhibition of cancer cells caused by LHPP in GBM [28]. The results related to the effects of LHPP in GBM suggest that it may be a potential therapeutic target.

3.5 LHPP and cervical cancer

In addition to being the most common gynecologic malignancy, cervical cancer also has the highest mortality rate among cancers [62,63]. Although its incidence and mortality have decreased significantly in recent decades with the development of techniques for diagnosis and treatment, the prognosis of patients with advanced-stage disease remains poor [64,65]. Zheng et al. found that LHPP expression was downregulated in clinical cervical cancer tumor tissues and cell lines and that patients with greater levels of LHPP expression showed a better prognosis. Increased expression of LHPP may be related to tumor size and lymphatic metastasis of cervical cancer. Researchers have also found that LHPP inhibits the proliferation and metastasis of cervical cancer cells through MMP-2, MMP-9, TGF-β1, fibronectin, Neuronal cadherin (N-cadherin), and vimentin and promotes apoptosis by inhibiting AKT activation [66]. In addition, inhibition of the cyclin D1/CDK4 pathway plays a key role in regulating tumor progression, and LHPP significantly suppresses the expression of cyclin D1 and CDK4 [67]. P27 and p53 perform significant functions in inhibiting tumor development. Some investigators have found that LHPP significantly increases the protein levels of p53 and p27 and inhibits the growth of cervical cancer [66,68]. These results suggest that LHPP is a prospective target for therapy development in the fight against cervical cancer.

3.6 LHPP and thyroid cancer

Thyroid carcinoma (TC) is the most commonly occurring malignant tumor of the thyroid gland and accounts for approximately 1% of all malignant tumors in the body. In recent decades, the incidence of TC has ranked eighth among cancers in China, and TC has been a heavy economic burden on society [^69–71]. Studies of TC revealed that LHPP expression was downregulated in TC tissues and cell lines [32]. Cellular autophagy is an evolutionarily conserved and important process in eukaryotes for the turnover of intracellular material and participates in a number of physiological and pathophysiological processes in tumors [72,73] LHPP enhances autophagy in TC cells in response to the regulation of BECN1 and LC3BI/II. The PI3K/AKT/mTOR signaling pathway is engaged in the progression of many cancers and plays an important role in the development of TC. Sun et al. showed that LHPP inhibits cell proliferation, migration, and invasion by regulating the AKT/AMPK/mTOR signaling pathway. Increased expression of LHPP may be related to the disease-free survival of TC. It was further shown that LHPP enhances autophagy in TC by regulating the AKT/AMPK/mTOR signaling pathway [32,74]. These results show that LHPP inhibits the progression of TC cells and indicate that LHPP may be a promising treatment target.

3.7 LHPP and bladder cancer

Bladder cancer (BC) ranks fourth and ninth in incidence among malignancies in men and women, respectively. In recent decades, the morbidity of BC has been increasing [^75–77]. Thus, it is essential to improve the understanding of the pathogenesis of and reveal new treatments for BC tumors. It has been reported that the protein and mRNA expression of LHPP in BC tissues is reduced [30]. Aerobic glycolysis, represented by the Warburg effect, is a metabolic marker of tumors [78,79]. In a recent study, knockdown of LHPP was found to lead to increased glucose consumption and lactate production in BC cells. Functional studies have demonstrated that LHPP inhibits the proliferation, metastasis, and invasion of BC cells through the regulation of the cell cycle proteins p21, p27, and cyclin B. The majority of research indicates that p65 activation enhances cancer progression. Some studies have shown that downregulation of LHPP activates p65 by enhancing AKT signaling [30,80,81]. These studies highlight the novel role of LHPP in suppressing BC cell function, and LHPP may serve as a powerful diagnostic and therapeutic target for BC.

3.8 LHPP and other malignant tumors

With the demonstration of LHPP as a tumor suppressor, many researchers have conducted in-depth studies of its regulatory mechanism and found aberrant expression of LHPP in melanoma, renal cell carcinoma (RCC), pancreatic cancer (PaCa), non-small-cell lung cancer (NSCLC), and laryngeal cancer (LC). In LC, LHPP expression is reduced in tumor tissues, and the prognosis of patients with high LHPP expression is significantly better. A gene set enrichment analysis (GSEA) suggested that LHPP may regulate glycolysis to inhibit the progression of LC [82]. Wu et al. found that LHPP was expressed at low levels in PaCa tissues and cell lines. Analysis of the clinical features suggests that the decrease in LHPP in PaCa may be associated with increased invasion of lymphatic tissue by cancer cells. Cell function studies show that LHPP inhibits the proliferation, migration, and invasion of PaCa cells. These effects may be related to the inhibition of snail, laminin-5, L1CAM, N-cadherin, and vimentin mRNA expression by LHPP. In addition, LHPP promotes PaCa cell apoptosis, which may be related to the regulation of the target proteins cIAP1, cleaved PARP, and cleaved Casp3 [34]. Increased expression of LHPP may be related to lymphatic metastasis of PaCa. Zhang et al. revealed that LHPP was also significantly downregulated in RCC tissues and cell lines and that LHPP was positively related to tumor size and metastasis in RCC patients. In addition, LHPP significantly suppressed the growth and metastasis of RCC cells. However, inhibition of LHPP led to opposite effects [26].. Further studies showed that miRNA-765, miRNA-21, and miRNA-144 can promote the proliferation, EMT, and invasion of RCC cells by downregulating LHPP [83]. Yang et al. showed that LHPP suppresses cell EMT, proliferation, and invasion via vimentin and E-cadherin in NSCLC cells. Further mechanistic studies revealed that miR-217 directly binds to the LHPP 3ʹUTR and that GAS5 directly binds miR-217 to regulate LHPP. These studies suggest that GAS5 enhances LHPP expression by directly binding to the miR-217 binding site in NSCLC [84]. The prognosis of tumor patients with low GAS5 expression is poor, and GAS5 expression is also associated with drug resistance [^85–88]. MiR-217 gene expression promotes the proliferation and metastasis of tumor cells [89]. LHPP inhibits the proliferation of melanoma B16-F10 cells by arresting the cell cycle at the G0/G1 transition. In addition, LHPP promotes apoptosis in melanoma cells through upregulation of the caspase 3 and fas genes. Further study of the mechanism revealed that LHPP overexpression suppresses the transcription of the H2afv, EZH2 and CDK8 genes in melanoma [90]. The H2AFV gene is potentially oncogenic and plays an important role in the tumor cell cycle and EMT [91]. Studies have shown that EZH2 is essential for the biological function of cancer cell lines, and CDK8 is a target and biomarker for cancer therapy [92,93]. In addition, investigators have used iDPP nanoparticles delivering LHPP plasmids to treat melanoma in vivo and in vitro. The results showed that the LHPP nanocomplex inhibits the proliferation and promotes the apoptosis of melanoma cells and causes minimal systemic toxicity [90].

4. Regulatory mechanisms of LHPP in cancers

The role of LHPP in the signaling pathways involved in cancer development has been comprehensively explored. As shown in Tables 1 and 2, Although the mechanism of LHPP is relatively less explored at present, LHPP seems to affect tumor progression in many cancer types through the regulation of the PI3K-Akt pathway. Therefore, we mainly discuss the mechanisms related to the effects of LHPP on the PI3K-Akt pathway. The PI3K/Akt signaling pathway plays an important role in tumor progression, including processes such as cell proliferation, apoptosis and metastasis. LHPP plays an important role in tumor metastasis by regulating the expression of its upstream and downstream genes. Mechanistic studies have shown that LHPP inhibits the phosphorylation of smad2/3 through the TGF-β1/PI3K/Akt signaling pathway [33]. Experiments in HCT-116 cells showed that the LHPP protein inhibits CRC cell growth by suppressing the PI3K/AKT signaling pathway and that overexpression of the LHPP protein suppresses the expression of the EGFR, cyclin-D1, and NF-κB proteins in HCT-116 cells [45]. In another paper, similar results also showed that LHPP can inhibit the growth and proliferation of CRC cells and promote their apoptosis through the PI3K/AKT signaling pathway [35]. Li et al. found that YTHDF2 enhances AKT phosphorylation in PCa by targeting the tumor suppressor LHPP for degradation. The researchers also found that LHPP is a novel tumor suppressor that inhibits the proliferation and metastasis of PCa cells by inhibiting the phosphorylation of vehicle AKT [56]. In addition, LHPP inhibits the proliferation and metastasis of GBM cells through the Akt signaling pathway [29]. Further mechanistic studies showed that LHPP inhibits the expression of MMP-2, MMP-9, TGF-β1, fibronectin, N-cadherin, and vimentin through the AKT pathway in cervical cancer cells [66]. Sun et al. showed that LHPP inhibits cell proliferation, migration, and invasion by regulating the AKT/AMPK/mTOR signaling pathway. It was further shown that LHPP enhances autophagy in TC by regulating the AKT/AMPK/mTOR signaling pathway [32,74]. Some studies have shown that downregulation of LHPP activates p65 by enhancing AKT signaling [30,80,81]. Wu et al. found that LHPP inhibited the mRNA expression of snail, laminin-5, L1CAM, N-cadherin, and vimentin through the AKT signaling pathway. In addition, LHPP can also regulate the target proteins cIAP1, cleaved PARP, and cleaved Casp3 through the AKT signaling pathway [34]. In conclusion, LHPP can regulate the PI3K/Akt signaling pathway, greatly affecting the signal transduction of cancer cells.

Table 1. Effect of LHPP upregulation in tumor cells

Cancer types	Effects of LHPP activation	Mechanism	Reference
Liver cancer	Inhibited proliferation	–	[27]
	Inhibited proliferation and metastasis	Decreased the expression of CCNB1, PKM2, MMP7 and MMP9	[31]
	Inhibited proliferation and metastasis and promoted apoptosis	MiR-765 targets the 3ʹUTR of LHPP	[39]
	Inhibited proliferation and metastasis	Suppression of the TGF-β signaling pathway	[33]
Colorectal cancer	Inhibited proliferation and metastasis and promoted apoptosis	Suppression of the PI3K-AKT signaling pathway	[35]
	Inhibited proliferation and promoted apoptosis	Purpurin interacts with LHPP	[45]
	Inhibited proliferation and metastasis	Suppression of the TGF-β/Smad signaling pathway	[48]
Prostate cancer	Inhibited proliferation and metastasis	Suppression of the AKT signaling pathway	[56]
Glioblastoma	Inhibited proliferation and metastasis	Downregulation of the AKT and Wnt/β-catenin signaling pathway	[29]
	Inhibited proliferation and the glycolysis	Increase PKM2 expression	[28]
Cervical cancer	Inhibited proliferation and metastasis, and promoted apoptosis	Inhibition of AKT activation	[66]
Thyroid cancer	Inhibited cell proliferation and metastasis and triggered autophagy	Regulation of the AKT/AMPK/mTOR signaling pathway	[32]
Bladder cancer	Inhibited proliferation and metastasis and suppressed glycolysis	Downregulation of p65 via reduced Akt signaling pathway	[30]
Pancreatic cancer	Inhibited proliferation and metastasis and promoted apoptosis	Inhibition AKT activation	[34]
Renal cell carcinoma	Inhibited proliferation and metastasis	–	[26]
	Inhibited proliferation and metastasis	MiRNA‐765, MiRNA‐21 and MiRNA‐144 targets the 3ʹUTR of LHPP	[83]
Non-small cell lung cancer	Inhibited proliferation and metastasis	MiR-217 targets the 3ʹUTR of LHPP	[84]
Melanoma	Inhibited proliferation and metastasis and promoted apoptosis	Suppression of the transcription of the H2AFV, EZH2 and CDK8 genes	[90]

Table 2. Effect of LHPP downregulation in tumor cells

Cancer types	Effects of LHPP deficiency	Mechanism	Reference
Liver cancer	Promoted proliferation	–	[27]
Colorectal cancer	Promoted proliferation and metastasis and Inhibited apoptosis	Activation of the PI3K-AKT and TGF-β/Smad signaling pathway	[35,48]
Prostate cancer	Promoted metastasis	MiR-346 targets the 3ʹUTR of LHPP	[57]
Glioblastoma	Promoted proliferation and metastasis	Upregulation of the AKT and Wnt/β-catenin signaling pathways	[29]
Cervical cancer	Promoted proliferation and metastasis and inhibited apoptosis	Activation of the AKT signaling pathway	[66]
Bladder cancer	Promoted proliferation and metastasis	Upregulation of p65 through potentiation AKT signaling pathway.	[30]
Pancreatic cancer	Promoted proliferation and metastasis and inhibited apoptosis	Activation of the AKT signaling pathway	[34]
Renal cell carcinoma	Promoted proliferation and metastasis	–	[83]

5. Conclusion

LHPP has been shown to be a tumor suppressor [27]. As a novel histidine phosphatase, LHPP is downregulated in various cancers and associated with clinical and pathological characteristics, including tumor stage, TNM stages, lymph node metastasis, Tumor size, and survival of cancer patients (Table 3). Functional studies have also shown that LHPP is highly expressed in tumors, and LHPP can inhibit tumor cell proliferation, metastasis, and glycolysis and promote apoptosis to regulate cancer progression. The proliferation and metastasis of tumor cells are important factors affecting cancer progression. Mechanistic studies have shown that LHPP competitively binds with microRNAs (such as miR-363-5p and miR-765), resulting in the abnormal expression of their downstream target genes (such as PKM2), and modulation of some classical signaling pathways (such as PI3K-AKT pathway) (Figure 2). Although many studies have shown that LHPP can inhibit tumorigenesis, the mechanism by which it inhibits tumor progression has not been studied in depth. In addition, although LHPP-loaded nanocarriers can inhibit the progression of melanoma cells, the toxicity and unpredictable side effects of nanoparticles still need to be further explored. LHPP can be used in combination with existing chemoradiotherapy to increase tumor sensitivity to existing therapies. The key challenges in this regard will be to find an effective method of targeting LHPP and an effective in vivo delivery method. To date, siRNA and other nucleic acid therapies have become increasingly mature and can successfully knock out the expression of LHPP in cells. Clinical trials have shown that combining small molecules to promote LHPP expression in cancer can be used as an effective strategy. With an increasing number of genomic studies on their roles in cancer pathogenesis and the improved success rate of nucleic acid therapy, LHPP and other genes will soon become viable therapeutic targets for cancer treatment. Therefore, researchers need to develop a comprehensive understanding of the mechanism of LHPP, explore how it regulates tumor progression, and provide further evidence to support the use of LHPP as a therapeutic target. Regardless, LHPP remains a promising cancer therapeutic target. Although the application of LHPP in vivo is currently relatively lacking, its therapeutic effect on tumors still deserves further exploration.

Figure 2. Molecular mechanism of LHPP.

Table 3. Clinical characteristics of LHPP in various tumors

Cancer types	Associated clinical features	Reference
Liver cancer	Overall survival and disease-free survival	[31,33]
Colorectal cancer	Tumor size, TNM stage, lymphatic metastasis	[35]
Prostate cancer	Lymphatic metastasis	[52]
Glioblastoma	Overall survival	[28]
Cervical cancer	Overall survival, tumor size, lymphatic metastasis	[62]
laryngeal cancer	Overall survival	[80]
Pancreatic cancer	Lymphatic metastasis	[34]
Thyroid carcinoma	Disease-free survival	[32]
Renal cell carcinoma	Tumor size, histological differentiation, T/N stage, Overall survival and disease-free survival	[26,83]

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Availability of data and materials

The datasets generated during and/or analysed during the current study are available in the [TIMER] repository.

Authors’ contributions

FH Wu and HW Ma analyzed and interpreted the data, and were major contributor in writing the manuscript. XL Wang, HZ Wei, W Zhang provided technical support. YC Zhang, who provided ideas and financial support, was our corresponding author. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

Supported by Science and technology projects in Cheng guan District of Lanzhou City (2014-4-4) and Lanzhou city science and technology development guidance plan project (No. 2019-ZD-71) and Gansu Province Youth Science and Technology Foundation (21JR1RA149).