Upregulated UHRF1 Promotes Bladder Cancer Cell Invasion by Epigenetic Silencing of KiSS1

Abstract

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), as an epigenetic regulator, plays important roles in the tumorigenesis and cancer progression. KiSS1 functions as a metastasis suppressor in various cancers, and epigenetic silencing of KiSS1 increases the metastatic potential of cancer cells. We therefore investigated whether UHRF1 promotes bladder cancer cell invasion by inhibiting KiSS1. The expression levels of UHRF1 and KiSS1 were examined by quantitative real-time PCR assay in vitro and in vivo. The role of UHRF1 in regulating bladder cancer metastasis was evaluated in bladder cancer cell. We found that UHRF1 levels are upregulated in most clinical specimens of bladder cancer when compared with paired normal tissues, and UHRF1 expression levels are significantly increased in primary tumors that subsequently metastasized compared with non-metastatic tumors. Forced expression of UHRF1 promotes bladder cancer cell invasion, whereas UHRF1 knockdown decreases cell invasion. Overexpression of UHRF1 increases the methylation of CpG nucleotides and reduces the expression of KiSS1. UHRF1 and KiSS1 expression level is negatively correlated in vivo and in vitro. Knockdown of KiSS1 promotes bladder cancer cell invasion. Importantly, forced expression of KiSS1 partly abrogates UHRF1-induced cell invasion. These data demonstrated that upregulated UHRF1 increases bladder cancer cell invasion by epigenetic silencing of KiSS1.

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

“…The SRA domain of UHRF1 specifically binds to hemi-methylated CpG following DNA replication, and recruits DNMT1 to methylate the newly synthesized DNA strand (29). UHRF1 is overexpressed and associated with tumor stages, and predicts poor prognosis in various types of cancer (15,21). UHRF1 has previously been identified as an oncogene in hepatocellular carcinoma (19,20).…”

“…Through interaction with other nuclear proteins, including Tip60, histone deacetylase and G9A, UHRF1 may function as a bridge between DNA methylation and the histone methylation (12). Furthermore, significant overexpression of UHRF1 has been observed in several types of human tumor, including breast (13,14), bladder (15), prostate (16) and lung cancer (17). The overexpression of UHRF1 has also been reported to reduce the radiosensitivity of human breast cancer cells and HeLa cells to γ-irradiation (18).…”

miR-128 downregulation promotes growth and metastasis of bladder cancer cells and involves VEGF-C upregulation

“…Approximately 50% of patients diagnosed with muscle-invasive bladder cancer (MIBC) develop distant metastases in the lungs and liver, resulting in poor 5-year survival rates (2,3). Currently, the advances in suitable therapy for enhancing survival rate are limited since the underlying mechanisms that result in tumor metastasis are not well understood.…”

UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation

“…14,15 UHRF1 increases the G1/S transition as the target of E2F transcription factor, 16 and upregulation of UHRF1 promotes cell cycle progression, cell proliferation and cell migration. [8][9][10]12,13 Our previous study demonstrated that UHRF1 is upregulated in GC tissues and that forced UHRF1 overexpression could promote GC invasion and metastasis. 17 However, the function and mechanism of UHRF1 in GC proliferation and carcinogenesis remain largely unknown.…”

“…3,4 In recent years, many investigations have focused on UHRF1 functions in various physiological and pathological processes. UHRF1 is upregulated in multiple types of cancers, including breast, 5 lung, 6,7 colorectal, 8,9 prostate, 10 bladder, 11,12 and liver cancer, 13 and a consensus has been reached that UHRF1 may be an important biomarker for cancer diagnosis and prognosis. Moreover, emerging evidence has indicated that overexpression of UHRF1 is involved in tumorigenesis and cancer progression.…”