Epigenetic mechanism and target therapy of UHRF1 protein complex in malignancies

Figures & data

Figure 1 Schematic representation of UHRF1 with structure–function domains in the maintenance of DNA methylation.

Notes: (A) Domain architecture of UHRF1 with their corresponding epigenetic function including DNA methylation and histone modification. (B) Conformational changes of UHRF1 from close to open state mediated by hmDNA.

Abbreviations: DNMT, DNA methyltransferases; H3K9me2/3, dimethylated or trimethylated H3K9; H3R2, unmethylated histone H3 at residue R2; hmDNA, hemi-methylated DNA; HAUSP, herpes virus-associated ubiquitin-specific protease; PBR, polybasic region; PHD, plant homeodomain; PI5P, phosphatidylinositol 5-phosphate; RING, really interesting new gene; SRA, SET and RING-associated domain; TTD, tandem tudor domain; UBL, ubiquitin-like domain.

Figure 2 Working model for dynamic regulation of UHRF1 macromolecular complex during cell cycle.

Notes: (A) The spatialization of UHRF1 macromolecular complex including UHRF1 at open state and other members of ECREM recruited into replication forks during S phase. (B) The separation of HAUSP from the complex owing to phosphorylation mediated by CDK1-cyclin B at the beginning of G2 phase. (C) Acetylation and ubiquitination of UHRF1 and DNMT1 by Tip60 due to release of HAUSP and HDAC1 from ECREM during G2-M phase. (D) The ubiquitination-mediated protein degradation of UHRF1 and DNMT1 in order to enter the normal cell cycle.

Abbreviations: DNMT, DNA methyltransferases; ECREM, epigenetic code replication machinery; HAUSP, herpes virus-associated ubiquitin-specific protease; HDAC1, histone deacetylase 1; PBR, polybasic region; PHD, plant homeodomain; RING, really interesting new gene; SRA, SET and RING-associated domain; Tip60, Tat-interactive protein; TTD, tandem tudor domain; UBL, ubiquitin-like domain; UHRF1, ubiquitin-like with PHD and RING finger domains 1; PCNA, proliferating cell nuclear antigen; CDK1, cyclin-dependent kinase 1.

Table 1 Inhibition of TSGs by overexpression of UHRF1 in various types of cancers

TSGs	Functions	Cancers
P16^INK4	Growth, metastasis, and apoptosis	Colorectal cancer [22219067] Cervical cancer [23688286] Glioblastoma [25550546]
BRCA1	DNA damage repair, transcription regulation, chromatin remodeling, cell cycle checkpoint control, and apoptosis	Breast cancer [19943104]
RUNX3	Hypoxia and immune cell maintenance	Hepatocellular carcinoma [26147747]
KISS1	Tumor differentiation, the depth of invasion, lymph node metastasis, and distant metastasis	Bladder cancer [25272010]
RASSF1	Proliferation, invasion, and apoptosis	Non-small-cell lung cancer [21351083]
MEG3	Proliferation	Hepatocellular carcinoma [25641194]
CDH4	Proliferation, invasion, and metastasis	Gastric cancer [26147747] [23982143]
Keap1	Oxidative stress and reductive stress	Pancreatic cancer [26497117]
KLF17	Invasion and epithelial–mesenchymal transition	Breast cancer [28744404]
SHP1	Tumor differentiation or muscular infiltration depth	Endometrial carcinoma [26597461]
CDX2	Lymph node metastasis and tumor, nodes, metastasis stage	Gastric cancer [26147747]
PPARG	Proliferation and migration and Wnt/β-catenin signaling pathway	Gastric cancer [26147747] Colorectal cancer [22286757]
FOXO4	Proliferation and metastasis	Gastric cancer [26147747]
RIP3	Cell survival, cell apoptosis, and cell necrosis	Colorectal cancer [28981102]
Slit3	Invasion and metastasis	Gastric cancer [23982143]
CDH1	Invasion and epithelial-to-mesenchymal transition	Prostate cancer [22330138] [29466696] Osteosarcoma [26548607]
IGFBP3	Colony formation, migration, and invasion	Prostate cancer [22330138] Hepatoblastoma [29507645]
GPX3	ROS, migration, invasion, metastasis	Prostate cancer [22330138]
UBE2L6	Apoptosis	Cervical cancer [29157076]
RGS2	Proliferation	Bladder cancer [25323766]
miR-145	Proliferation, migration and invasion	Non-small-cell lung cancer [25961369]

Abbreviations: UHRF1, ubiquitin-like with PHD and RING finger domains 1; TSGs, tumor suppressor genes; ROS, reactive oxygen species.

Table 2 Regulation of UHRF1 by microRNA in various types of cancers

mRNAs	Functions	Cancers
miR-124	Proliferation, motility, angiogenesis	Bladder cancer [26310391]
miR-9	Proliferation, apoptosis	Colorectal cancer [25940709]
miR-101	Migration, invasion	Renal cell cancer [27487138]
miR-378	Proliferation, apoptosis	Medulloblastoma [28901497]
miR-193a-3p	Metastasis	Non-small-cell lung cancer [25833338]
miR-145-5 p/miR-145-3 p	Proliferation, apoptosis, migration, invasion	Bladder cancer [27628846]
miR-146a/b	Metastasis	Gastric cancer [23982143] Renal cell carcinoma [26859141]

Abbreviation: UHRF1, ubiquitin-like with PHD and RING finger domains 1.