UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest

Qin,Yiyu; Wang,Jiandong; Gong,Wei; Zhang,Mingdi; Tang,Zhaohui; Zhang,Jun; Quan,Zhiwei

doi:10.3892/or.2014.3145

UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest

Authors:
- Yiyu Qin
- Jiandong Wang
- Wei Gong
- Mingdi Zhang
- Zhaohui Tang
- Jun Zhang
- Zhiwei Quan
View Affiliations

Affiliations: Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
Published online on: April 23, 2014 https://doi.org/10.3892/or.2014.3145
Pages: 2635-2643

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1), overexpressed in various human malignancies, functions as an important regulator in cell proliferation and epigenetic regulation. Depletion of UHRF1 has shown potential antitumor activities in several types of cancer. However, the role of UHRF1 in gallbladder cancer (GBC) has not been investigated. RT-PCR, western blotting and immunohistochemistry were performed to examine UHRF1 expression at mRNA and protein levels in GBC tissues and cell lines. UHRF1 siRNA and UHRF1 shRNA were used to deplete the expression of UHRF1. The results showed that UHRF1 was overexpressed in GBC and its expression correlated with advanced TNM stage and presence of lymph node metastasis. UHRF1 depletion in GBC-SD and NOZ cells markedly inhibited proliferation, migration in vitro and the ability of these cells to form tumors in vivo. UHRF1 depletion upregulated the expression of PML and triggered extrinsic and intrinsic apoptotic pathways by promoting the expression of FasL/FADD, bax, cytosolic cytochrome c, cleaved caspase-8, -9 and -3 and cleaved PRAP and by suppressing bcl-2 expression in GBC-SD and NOZ cells. In addition, UHRF1 depletion induced cell cycle arrest at G1/S transition by inducing p21 in a p53-independent manner in GBC-SD and NOZ cells. Our findings suggest that UHRF1 is involved in the proliferation and migration of GBC cells and may serve as a biomarker or even a therapeutic target for GBC.

View Figures

View References

1	Nagorney DM and McPherson GA: Carcinoma of the gallbladder and extrahepatic bile ducts. Semin Oncol. 15:106–115. 1988.PubMed/NCBI
2	Zhu AX, Hong TS, Hezel AF and Kooby DA: Current manage- ment of gallbladder carcinoma. Oncologist. 15:168–181. 2010. View Article : Google Scholar
3	Takahashi T, Shivapurkar N, Riquelme E, et al: Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res. 10:6126–6133. 2004. View Article : Google Scholar : PubMed/NCBI
4	Unoki M, Nishidate T and Nakamura Y: ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene. 23:7601–7610. 2004. View Article : Google Scholar : PubMed/NCBI
5	Jeanblanc M, Mousli M, Hopfner R, et al: The retinoblastoma gene and its product are targeted by ICBP90: a key mechanism in the G1/S transition during the cell cycle. Oncogene. 24:7337–7345. 2005. View Article : Google Scholar : PubMed/NCBI
6	Geng Y, Gao Y, Ju H and Yan F: Diagnostic and prognostic value of plasma and tissue ubiquitin-like, containing PHD and RING finger domains 1 in breast cancer patients. Cancer Sci. 104:194–199. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wang F, Zhang P, Ma Y, et al: NIRF is frequently upregulated in colorectal cancer and its oncogenicity can be suppressed by let-7a microRNA. Cancer Lett. 314:223–231. 2012. View Article : Google Scholar : PubMed/NCBI
8	Unoki M, Kelly JD, Neal DE, Ponder BA, Nakamura Y and Hamamoto R: UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer. Br J Cancer. 101:98–105. 2009. View Article : Google Scholar : PubMed/NCBI
9	Unoki M, Daigo Y, Koinuma J, Tsuchiya E, Hamamoto R and Nakamura Y: UHRF1 is a novel diagnostic marker of lung cancer. Br J Cancer. 103:217–222. 2010. View Article : Google Scholar : PubMed/NCBI
10	Babbio F, Pistore C, Curti L, et al: The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression. Oncogene. 31:4878–4887. 2012. View Article : Google Scholar : PubMed/NCBI
11	Yang C, Wang Y, Zhang F, et al: Inhibiting UHRF1 expression enhances radiosensitivity in human esophageal squamous cell carcinoma. Mol Biol Rep. 40:5225–5235. 2013. View Article : Google Scholar : PubMed/NCBI
12	Pi JT, Lin Y, Quan Q, Chen LL, Jiang LZ, Chi W and Chen HY: Overexpression of UHRF1 is significantly associated with poor prognosis in laryngeal squamous cell carcinoma. Med Oncol. 30:6132013. View Article : Google Scholar : PubMed/NCBI
13	Tien AL, Senbanerjee S, Kulkarni A, et al: UHRF1 depletion causes a G₂/M arrest, activation of DNA damage response and apoptosis. Biochem J. 435:175–185. 2011.PubMed/NCBI
14	Arima Y, Hirota T, Bronner C, et al: Down-regulation of nuclear protein ICBP90 by p53/p21^Cip1/WAF1-dependent DNA damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes Cells. 9:131–142. 2004.PubMed/NCBI
15	Lazcano-Ponce EC, Miquel JF, Muñoz N, et al: Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin. 51:349–364. 2001. View Article : Google Scholar : PubMed/NCBI
16	Jenkins Y, Markovtsov V, Lang W, et al: Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol Biol Cell. 16:5621–5629. 2005. View Article : Google Scholar : PubMed/NCBI
17	Porter AG and Jänicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6:99–104. 1999. View Article : Google Scholar : PubMed/NCBI
18	Vermeulen K, Van Bockstaele DR and Berneman ZN: Apoptosis: mechanisms and relevance in cancer. Ann Hematol. 84:627–639. 2005. View Article : Google Scholar : PubMed/NCBI
19	Guan D, Factor D, Liu Y, Wang Z and Kao HY: The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein. Oncogene. 32:3819–3828. 2013. View Article : Google Scholar
20	Chang HJ, Yoo BC, Kim SW, Lee BL and Kim WH: Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas. Pathol Oncol Res. 13:326–335. 2007. View Article : Google Scholar : PubMed/NCBI
21	Krieghoff-Henning E and Hofmann TG: Role of nuclear bodies in apoptosis signalling. Biochim Biophys Acta. 1783:2185–2194. 2008. View Article : Google Scholar : PubMed/NCBI
22	Reineke EL, Liu Y and Kao HY: Promyelocytic leukemia protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1. J Biol Chem. 285:9485–9492. 2010. View Article : Google Scholar : PubMed/NCBI
23	Kim WH, Kang KH, Kim MY and Choi KH: Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. Biochem Cell Biol. 78:127–135. 2000. View Article : Google Scholar : PubMed/NCBI
24	Zuo S, Liu C, Wang J, et al: IGFBP-rP1 induces p21 expression through a p53-independent pathway, leading to cellular senescence of MCF-7 breast cancer cells. J Cancer Res Clin Oncol. 138:1045–1055. 2012. View Article : Google Scholar : PubMed/NCBI
25	Shen Y: Advances in the development of siRNA-based therapeutics for cancer. IDrugs. 11:572–578. 2008.PubMed/NCBI
26	Unoki M, Kumamoto K and Harris CC: ING proteins as potential anticancer drug targets. Curr Drug Targets. 10:442–454. 2009. View Article : Google Scholar : PubMed/NCBI