title: UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation.
abstract: Epigenetic changes play significant roles in cancer development. UHRF1, an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene (TSG) silencing in several cancers. In a previous study, we found that UHRF1 promoted gastric cancer (GC) invasion and metastasis. However, the role and underlying mechanism of UHRF1 in GC carcinogenesis remain largely unknown. In the present study, we investigated UHRF1 expression and function in GC proliferation and explored its downstream regulatory mechanism. The results demonstrated that UHRF1 overexpression was an independent and significant predictor of GC prognosis. Downregulation of UHRF1 suppressed GC proliferation and growth in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Furthermore, downregulation of UHRF1 reactivated 7 TSGs, including CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML, via promoter demethylation. These results provide insight into the GC proliferation process, and suggest that targeting UHRF1 represents a new therapeutic approach to block GC development.
authors.affiliation: a Department of Medical Affairs ; The 88th Hospital of PLA ; Tai'an , China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Yulong
authors.initials: Y
authors.lastname: Shang
authors.forename: Zhi'an
authors.initials: Z
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunlei
authors.initials: C
authors.lastname: Lv
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Zhao
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Liu
authors.forename: Naiyi
authors.initials: N
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
mesh_terms: D000368:Aged; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: BRCA, breast cancer; CDH4, cadherin 4; CDKN2A, cyclin-dependent kinase inhibitor 2A; CDX2, caudal type homeobox 2; DNA methylation; DNMT, DNA methyltransferase; FOXO, forkhead box O; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GC, gastric cancer; GO, gene ontology; MSP, methylation-specific PCR; NC, negative control; PBS, phosphate buffered saline; PI, propidium iodide; PLA, Chinese People's Liberation Army; PML, promyelocytic leukemia; PPARG,peroxisome proliferator-activated receptor gamma; RB, retinoblastoma protein; RUNX3, runt-related transcription factor 3; TSG, tumor suppressor gene; UHRF1; UHRF1, ubiquitin-like containing PHD ring finger 1; gastric cancer; mRNA, messenger RNA; proliferation; qRT-PCR, quantitative reverse transcription–polymerase chain reaction; shRNA, short hairpin RNA; tumor suppressor gene