Role of RNA binding proteins of the Drosophila behavior and human splicing (DBHS) family in health and cancer

Figures & data

Figure 1. Representation of domain structures of human Drosophila behavior/human splicing (DBHS) family proteins. Human DBHS family consists of polypyrimidine tract-binding protein-associated splicing factor (PSF)/splicing factor proline/glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO)/nuclear RNA-binding protein, 54 kDa (p54^nrb) and paraspeckle component 1 (PSPC1)/paraspeckle protein 1 (PSP1). DBHS family proteins contain the conserved DBHS region that is involved in RNA recognition and the formation of DBHS family protein homodimer and heterodimer. The N- and C-terminal regions adjacent to the DBHS region are low-complexity regions (LCRs) that are involved in the regulation of phase separation. DBD, DNA-binding domain; LCR, low-complexity region; NOPS, NonA/paraspeckle domain; RRM1, RNA recognition motif 1; RRM2, RNA recognition motif 2.

Figure 2. Schematic representation of roles of DBHS family proteins in cells and tissues. (a) polypyrimidine tract-binding protein-associated splicing factor (PSF)/splicing factor proline/glutamine rich (SFPQ) regulates neural gene expression posttranscriptionally and transcriptionally. SFPQ-mediated gene regulation plays important roles in the development and homeostasis of neural tissues and cells and in the pathophysiology of neural diseases. SFPQ is also involved in the development of skeletal muscle and modulation of T cell function. (b) Non-POU domain-containing octamer-binding protein (NONO) posttranscriptionally regulates the rhythmic expression of glucose metabolism-related genes, such as glucokinase (Gck) and glucose transporter type 2, liver (Glut2), and fat metabolism genes, such as ATP-citrate-lyase (Acly) and mitochondrial glycerol-3-phosphate acyltransferase (Gpam), in liver, contributing to the homeostasis of glucose and fat metabolism. In addition, NONO promotes the ten-eleven translocation 1 (TET1)-mediated 5-hydroxymethylcytosine modification of neural genes, facilitating neural differentiation of embryonic stem cells (ESCs). Paraspeckle component 1 (PSPC1) enhances nuclear export of mRNAs associated with adipogenesis to promote adipocyte differentiation. In addition, PSPC1 forms a complex with a 5-methylcytosine (5mC) dioxygenase ten-eleven translocation 2 (TET2) and is involved in transcriptional and posttranscriptional regulation of endogenous retrovirus (ERV), such as murine endogenous retrovirus-L (MERVL) and class II ERVs. NONO and PSPC1 transcriptionally upregulate the expression level of aldehyde dehydrogenase 1 family member a1 (ALDH1A1) to protect Sertoli cells from a toxicant mono-(2-ethylhexyl) phthalate (MEHP). NONO/PSPC1 complex is also suggested to be involved in epigenetic regulation of bivalent genes during the transition from embryonic stem cells (ESCs) to epiblast-like stem cells (EpiLCs). Posttranscriptional and transcriptional target genes of DBHS family proteins are shown in red and green, respectively. Genes regulated by DBHS family proteins during subcellular mRNA transport are shown in blue. Acly, ATP-citrate-lyase; Acsl1, acyl-coenzyme a synthetase long chain family member 1; ALDH1A1, aldehyde dehydrogenase 1 family member a1; APP, amyloid-β precursor protein; Bclw, B-cell lymphoma-2 (bcl-2)-like 2; CaMKIIα, calmodulin-dependent protein kinase II α; CD45, cluster of differentiation 45; DBHS, Drosophila behavior and human splicing; Ebf1, early B-cell factor 1; EpiLCs, epiblast-like stem cells; ERV, endogenous retrovirus; ESCs, embryonic stem cells; Gck, glucokinase; Glut2, glucose transporter type 2, liver; Gpam, mitochondrial glycerol-3-phosphate acyltransferase; KIF5, kinesin family member 5; Lmnb2, lamin B2; MAPT, microtubule associated protein tau; MEHP, mono-(2-ethylhexyl) phthalate; MERVL, murine endogenous retrovirus-L; NMHC II-B, nonmuscle myosin heavy chain II-B; NONO, non-POU domain-containing octamer-binding protein; Pparg, peroxisome proliferator activated receptor γ; PSPC1, paraspeckle component 1; Scd1, stearoyl-coenzyme A desaturase-1; SFPQ, splicing factor proline/glutamine rich; 3R-T, 3-repeat tau; 4R-T, 4-repeat tau; TET1, ten-eleven translocation 1; TET2, ten-eleven translocation 2.

Table 1. Roles of DBHS family proteins in gene regulation in cells and tissues.

DBHS family protein	Target genes	Cell type	Function
Regulation of pre-mRNA splicing/RNA processing
SFPQ	MAPT	Neural cells	Promotes exon 10 exclusion to decrease 4R-T/3R-T [45,46]
	APP	Neural cells	Posttranscriptionally upregulates APP levels [47,48]
	NMHC II-B	Neural cells	Promotes exon N30 inclusion of NMHC II-B, contributing to normal migration of facial neurons [49]
	CD45	T cells	Promotes exclusion of CD45 variable exons, modulating TCR signalling [50,51]
NONO	glucose metabolism-related genes such as Gck and Glut2, and fat metabolism-related genes such as Acly and Gpam	Hepatic cells	Posttranscriptionally regulates the rhythmic expression of its target RNAs to modulate glucose and fat metabolism [52]
PSPC1	MERVL	ESCs	Posttranscriptionally downregulates the expression of MERVL through TET2-mediated 5-hydroxymethylcystosine modification of MERVL transcripts [53]
Transcriptional regulation
PSPC1	MERVL and class II ERVs	ESCs	Epigenetically regulates MERVL and class II ERVs [53]
SFPQ	Longer genes (≥100 kb)	Neural cells Skeletal muscles	Promotes the transcriptional elongation on longer genes [54–56]
NONO	Genes associated with neural differentiation	ESCs	Promotes the recruitment of TET1 onto neural genes, increasing TET1-mediated 5-hydroxymethylcystosine modification of these genes [57]
NONO and PSPC1	Some bivalent genes, including Eomes and Fgf5	ESCs EpiLCs	Repress the transcription of some bivalent genes by promoting the recruitment of PRC2 to these gene promoters [58]
	ALDH1A1	Sertoli cells	Promote the transcription of ALDH1A1 in Sertoli cells, contributing to survival of the cells treated with a toxicant MEHP [59]
Subcellular RNA transport
SFPQ	CaMKIIα, Lmnb2, and Bclw	Neural cells	Modulates axonal transport of these gene transcripts [60–62]
PSPC1	Adipogenesis-related genes such as Ebf1, Pparg, Acsl1, and Scd1	Differentiating adipocytes	Facilitates nuclear export of target mRNAs to promote adipocyte differentiation [63]

Acly, ATP-citrate-lyase; Acsl1, acyl-coenzyme A synthetase long chain family member 1; ALDH1A1, aldehyde dehydrogenase 1 family member a1; APP, amyloid-β precursor protein; Bclw, B-cell lymphoma-2 (Bcl-2)-like 2; CaMKIIα, calmodulin-dependent protein kinase II α; CD45, cluster of differentiation 45; DBHS, Drosophila behavior and human splicing; Ebf1, early B-cell factor 1; Eomes, eomesodermin; EpiLCs, epiblast-like stem cells; ERV, endogenous retrovirus; ESCs, embryonic stem cells; Fgf5, fibroblast growth factor 5; Gck, glucokinase; Glut2, glucose transporter type 2, liver; Gpam, mitochondrial glycerol-3-phosphate acyltransferase; KIF5, kinesin family member 5; Lmnb2, lamin B2; MAPT, microtubule associated protein tau; MEHP, mono-(2-ethylhexyl) phthalate; MERVL, murine endogenous retrovirus-L; NMHC II-B, nonmuscle myosin heavy chain II-B; NONO, non-POU domain-containing octamer-binding protein; Pparg, peroxisome proliferator activated receptor γ; PRC2, polycomb repressive complex 2; PSPC1, paraspeckle component 1; Scd1, stearoyl-coenzyme A desaturase-1; SFPQ, splicing factor proline/glutamine rich; 3 R-T, 3-repeat tau; 4 R-T, 4-repeat tau; TCR, T cell receptor; TET1, ten-eleven translocation 1; TET2, ten-eleven translocation 2.

Table 2. Roles of DBHS family proteins in gene regulation in cancers.

DBHS family protein	Target genes	Cancer type	Function
Regulation of pre-mRNA splicing/RNA processing
SFPQ, NONO	AR	Prostate cancer	Promote the splicing of AR to upregulate the expression levels of full-length AR and AR-V7 [78]
	Multiple spliceosome genes, including SF1 and SF3B2	Prostate cancer	Posttranscriptionally upregulate the expression levels of some spliceosome genes [78]
	BIN1	Hepatocellular carcinoma	Promote exon 12a inclusion to produce BIN-L isoform [79]
	glycolysis-associated genes, including PGK1 and LDHA	Hepatocellular carcinoma	Promote splicing of some glycolysis-related genes to enhance aerobic glycolysis [80]
	SETMAR	Bladder cancer	Promote exon 2 inclusion of SETMAR to produce SETMAR-L isoform [81]
	CASP9	Ovarian cancer	Modulate alternative splicing of CASP9 to upregulate the abundance of CASP9b isoform [82]
SFPQ, PSPC1	ESR1 and SCFD2	ER-positive breast cancer	Posttranscriptionally upregulate the expression levels of ESR1 and SCFD2 [83,84]
SFPQ	ASPM and TRA2B	ER-positive breast cancer	Posttranscriptionally upregulates the expression levels of ASPM and TRA2B [83]
	SLC7A11	Glioblastoma	Promotes the splicing of SLC7A11 to suppress ferroptosis [85]
NONO, PSPC1	GPX1	Glioblastoma	Promote the splicing of GPX1 to suppress apoptosis [18]
NONO	SKP2 and E2F8	Breast cancer	Posttranscriptionally upregulates the expression level of SKP2 and E2F8 [86]
	STAT3	Breast cancer	Binds to and Increases STAT3 mRNA [17]
	MycN	Neuroblastoma	Posttranscriptionally upregulates the expression level of MycN [87]
	GATA2 and HAND2	Neuroblastoma	Promotes the splicing of GATA2 and HAND2 [88]
	HIF-1/2 target genes	Hepatocellular carcinoma	Posttranscriptionally modulates the expression level of HIF-1/2 target genes [89]
Transcriptional and epigenetic gene regulation
SFPQ, NONO	Some genes including CTBP1 and p53	Prostate cancer	Repress the target gene transcription by promoting the histone H3 deacetylation [90]
SFPQ	CXCL8	Glioblastoma	Suppresses the transcription of CXCL8 [91]
	FOSL	Nasopharyngeal cancer	Activates the transcription of FOSL1 [92]
NONO	TAZ target genes	Glioblastoma	Promotes TAZ-mediated transcriptional gene regulation [93]
	HIF-1/2 target genes	Hepatocellular carcinoma	Promotes HIF-1/2-mediated transcriptional gene regulation [89]
	Ets-1	Gastric cancer	Upregulates the transcription of Ets-1 [94]
PSPC1	EMT- and cell stemness-related genes, including Snail and Nanog	Breast cancer Hepatocellular carcinoma Lung cancer	Forms a complex with Smad2/3 and modulates the recruitment of Smad2/3 to target genes [95]
	β-catenin target genes	Hepatocellular carcinoma	Promotes β-catenin-mediated transcriptional gene regulation [96]
Regulation of IRES-mediated translation
SFPQ	CK1α	HCT-116 colorectal cancer cells	Promotes the IRES activity of CK1α [97]
SFPQ	RUNX2 and VEGFA	Colorectal cancer	Suppresses the IRES activity of RUNX2 by sequestering PTBP2 [98]
SFPQ	c-Myc	Cervical cancer	Suppresses the IRES activity of c-Myc by sequestering PTB [99]

AR, androgen receptor; ASPM, assembly factor for spindle microtubules; BIN1, bridging integrator 1; CASP9, caspase 9; CK1α, casein kinase 1 α; CRPC, castration-resistant prostate cancer; CTBP1, C-terminal binding protein 1; CXCL8, C-X-C motif chemokine ligand 8; DBHS, Drosophila behavior and human splicing; E2F8, E2F transcription factor 8; ER, oestrogen receptor; ESR1, estrogen receptor 1; Ets-1, v-ets erythroblastosis virus E26 oncogene homolog 1; FOSL1, FOS like antigen 1; GPX1, glutathione peroxidase 1; HIF-1/2, hypoxia-inducible factor-1/2; IRES, internal ribosome entry site; LDHA, lactate dehydrogenase A; NONO, non-POU domain-containing octamer-binding protein; Oct4, octamer-binding protein 4; PGK1, phosphoglycerate kinase 1; PSPC1, paraspeckle component 1; PTB, polypyrimidine tract-binding protein; PTBP2, polypyrimidine tract-binding protein 2; RUNX2, runt-related transcription factor 2; SCFD2, sec1 family domain-containing 2; SETMAR, SET domain and mariner transposase fusion protein; SF1, splicing factor 1; SF3B2, splicing factor 3b subunit 2; SFPQ, splicing factor proline/glutamine rich; SKP2, S-phase-associated kinase 2; SLC7A11, solute carrier family 7 member 11; Smad2/3, Sma- and Mad-related protein 2/3; Sox2, SRY-box transcription factor 2; STAT3, signal transducer and activator of transcription 3; TAZ, transcription factor PDZ-binding motif; TGFB1, transforming growth factor-β1; TNBC, triple-negative breast cancer; VEGFA, vascular endothelial growth factor A.

Figure 3. Diagram of gene regulation by DBHS family proteins in cancers. Posttranscriptional and transcriptional target genes of DBHS family proteins are shown in red and green, respectively. Genes regulated by DBHS family proteins during the internal ribosome entry site (IRES)-mediated translation are shown in orange. AR, androgen receptor; ASPM, assembly factor for spindle microtubules; BIN1, bridging integrator 1; CASP9, caspase 9; CK1α, casein kinase 1 α; CRPC, castration-resistant prostate cancer; CTBP1, C-terminal binding protein 1; CXCL8, C-X-C motif chemokine ligand 8; E2F8, E2F transcription factor 8; ER, oestrogen receptor; ESR1, estrogen receptor 1; Ets-1, v-ets erythroblastosis virus E26 oncogene homolog 1; FOSL1, FOS like antigen 1; GATA2, GATA-binding protein 2; GPX1, glutathione peroxidase 1; HAND2, heart and neural crest derivatives expressed 2; HIF-1/2, hypoxia-inducible factor-1/2; LDHA, lactate dehydrogenase A; MycN, neuroblastoma MYC oncogene; NONO, non-POU domain-containing octamer-binding protein; Oct4, octamer-binding protein 4; PGK1, phosphoglycerate kinase 1; PSPC1, paraspeckle component 1; RUNX2, runt-related transcription factor 2; SCFD2, sec1 family domain-containing 2; SETMAR, SET domain and mariner transposase fusion protein; SFPQ, splicing factor proline/glutamine rich; SKP2, S-phase-associated kinase 2; SLC7A11, solute carrier family 7 member 11; SMAD3, Sma- and Mad-related protein 3; Sox2, SRY-box transcription factor 2; STAT3, signal transducer and activator of transcription 3; TAZ, transcription factor PDZ-binding motif; TGFB1, transforming growth factor-β1; TNBC, triple-negative breast cancer; VEGFA, vascular endothelial growth factor A.

Table 3. Small molecules targeting DBHS family proteins and their tumour-suppressive effects.

Small molecule	Target DBHS family protein	Binding site on target DBHS family protein	Effects on target DBHS family protein	Tumor-suppressive effects	Clinical application
No. 10–3 (7,8-dihydroxy-4- (4-methoxyphenyl) chromen-2-one)	SFPQ	The groove between coiled-coil domain and RNA-binding domain of SFPQ	Inhibits RNA binding of SFPQ	Suppresses in vitro proliferation of 22 Rv1 CRPC model cells and tamoxifen-resistant breast cancer cells [15] Impairs in vivo tumour growth of CRPC mouse models [15]	–
C-65 (4-[2-(3H-Imidazol[4,5-b] pyridib-2-ylsulfanyl) -acetylamino]-benzonic acid isopropyl ester)	SFPQ	Unknown	Inhibits RNA binding of SFPQ	Suppresses in vitro proliferation of 22 Rv1 CRPC model cells and tamoxifen-resistant breast cancer cells [16] Impairs in vivo tumour growth of CRPC mouse models [16]	–
Auranofin (1-Thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate)	NONO	Unknown	Decreases NONO expression level	Suppresses in vitro proliferation of MDA-MB-231 triple-negative breast cancer cells and glioblastoma cells [17,18] Impairs in vivo tumour growth of glioblastoma mouse models [18]	a treatment of rheumatoid arthritis [138]
(R)-SKBG-1 ((R)-4-(2-chloroacetyl) -N-(4-methoxybenzyl) −1-((4-methoxyphenyl) sulfonyl)piperazine-2 -carboxamide)	NONO	Cysteine 145 on NONO (covalent binding)	Enhances RNA binding of NONO	Suppresses in vitro proliferation of 22 Rv1 CRPC model cells and ER-positive MCF-7 breast cancer cells [19]	–

CRPC, castration-resistant prostate cancer; DBHS, Drosophila behavior and human splicing; ER, oestrogen receptor; NONO, non-POU domain-containing octamer-binding protein; SFPQ, splicing factor proline/glutamine rich.

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