UHRF1 expression is upregulated and associated with cellular proliferation in colorectal cancer

Kofunato,Yasuhide; Kumamoto,Kensuke; Saitou,Katsuharu; Hayase,Suguru; Okayama,Hirokazu; Miyamoto,Kotaro; Sato,Yu; Katakura,Kyoko; Nakamura,Izumi; Ohki,Shinji; Koyama,Yoshihisa; Unoki,Motoko; Takenoshita,Seiichi

doi:10.3892/or.2012.2064

UHRF1 expression is upregulated and associated with cellular proliferation in colorectal cancer

Authors:
- Yasuhide Kofunato
- Kensuke Kumamoto
- Katsuharu Saitou
- Suguru Hayase
- Hirokazu Okayama
- Kotaro Miyamoto
- Yu Sato
- Kyoko Katakura
- Izumi Nakamura
- Shinji Ohki
- Yoshihisa Koyama
- Motoko Unoki
- Seiichi Takenoshita
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Affiliations: Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, Division of Epigenomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
Published online on: September 27, 2012 https://doi.org/10.3892/or.2012.2064
Pages: 1997-2002

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Abstract

Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) binds to methylated promoters of a number of tumor-suppressor genes, including p16INK4A and p14ARF, by forming complexes with DNA methyltransferases and HDAC1, resulting in the induction of carcinogenesis. Altered UHRF1 expression has been demonstrated in various types of cancers. Previous reports indicate that UHRF1 expression is regulated by E2F-1 expression. We investigated UHRF1 expression using immunohistochemical staining in 231 colorectal cancer and 40 adenoma specimens, analyzed the relationship between UHRF1 expression and clinicopathological findings and the association between UHRF1 and E2F-1 expression. To better understand the biological function of UHRF1 in colorectal cancer, knockdown of UHRF1 expression was performed using siRNA methods. High UHRF1 expression was observed in 152 of 231 (65.8%) colorectal cancer patients, and was detected in 35 of 40 adenoma specimens samples (87.5%). UHRF1 staining was detected in the nucleus of cancer cells, while it was not detected in colonic normal mucosa. High UHRF1 expression was significantly observed in right compared with left hemicolon cancer (p=0.008). Moreover, high UHRF1 expression tended to be associated with depth of invasion (p=0.051). UHRF1 expression was significantly associated with E2F-1 expression (p<0.0001). Knockdown of UHRF1 expression suppressed cellular growth in colon cancer cell lines, HCT116 and SW620. In conclusion, we demonstrated that UHRF1 expression was upregulated in approximately two-thirds of colorectal cancer specimens and was particularly expressed in right compared with left hemicolon cancer. Moreover, knockdown of UHRF1 expression induced growth inhibition in colon cancer cell lines. UHRF1 may be involved in cellular proliferation and molecular pathogenesis of colorectal cancer in the right hemicolon.

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1	Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 26:2013–2019. 2008. View Article : Google Scholar : PubMed/NCBI
2	Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, et al: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 27:663–671. 2009. View Article : Google Scholar : PubMed/NCBI
3	Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 28:4697–4705. 2010. View Article : Google Scholar
4	Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 359:1757–1765. 2008. View Article : Google Scholar : PubMed/NCBI
5	Hopfner R, Mousli M, Jeltsch JM, Voulgaris A, Lutz Y, Marin C, Bellocq JP, Oudet P and Bronner C: ICBP90, a novel human CCAAT bonding protein, involved in the regulation of topoisomerase II alpha expression. Cancer Res. 60:121–128. 2000.PubMed/NCBI
6	Mousli M, Hopfner R, Abbady AQ, Monté D, Jeanblanc M, Oudet P, Louis B and Bronner C: ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. Br J Cancer. 89:120–127. 2003. View Article : Google Scholar : PubMed/NCBI
7	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
8	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
9	Crnogorac-Jurcevic T, Gangeswaran R, Bhakta V, Capurso G, Lattimore S, Akada M, Sunamura M, Prime W, Campbell F, Brentnall TA, et al: Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma. Gastroenterology. 129:1454–1463. 2005. View Article : Google Scholar : PubMed/NCBI
10	Oba-Shinjo SM, Bengtson MH, Winnischofer SM, Colin C, Vedoy CG, de Mendonça Z, Marie SK and Sogayar MC: Identification of novel differentially expressed genes in human astrocytomas by cDNA representational difference analysis. Brain Res Mol Brain Res. 140:25–33. 2005. View Article : Google Scholar : PubMed/NCBI
11	Lorenzato M, Caudroy S, Bronner C, Evrard G, Simon M, Durlach A, Birembaut P and Clavel C: Cell cycle and/or proliferation markers: what is the best method to discriminate cervical high-grade lesions? Hum Pathol. 36:1101–1107. 2005. View Article : Google Scholar : PubMed/NCBI
12	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
13	Unoki M, Brunet J and Mousli M: Drug discovery targeting epigenetic codes: the great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis. Biochem Pharmacol. 78:1279–1288. 2009. View Article : Google Scholar
14	Arima Y, Hirota T, Bronner C, Mousli M, Fujiwara T, Niwa S, Ishikawa H and Saya H: Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes Cells. 9:131–142. 2004. View Article : Google Scholar : PubMed/NCBI
15	Trotzier MA, Bronner C, Bathami K, Mathieu E, Abbady AQ, Jeanblanc M, Muller CD, Rochette-Egly C and Mousli M: Phosphorylation of ICBP90 by protein kinase A enhances topoisomerase II alpha expression. Biochem Biophys Res Commun. 319:590–595. 2004. View Article : Google Scholar : PubMed/NCBI
16	Bostick M, Kim JK, Estève PO, Clark A, Pradhan S and Jacobsen SE: UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 317:1760–1764. 2007. View Article : Google Scholar : PubMed/NCBI
17	Arita K, Ariyoshi M, Tochio H, Nakamura Y and Shirakawa M: Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature. 455:818–821. 2008. View Article : Google Scholar : PubMed/NCBI
18	Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, Arrowsmith CH and Dhe-Paganon S: Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature. 455:822–825. 2008. View Article : Google Scholar : PubMed/NCBI
19	Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE and Cheng X: The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature. 455:826–829. 2008. View Article : Google Scholar : PubMed/NCBI
20	Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, Shinga J, Mizutani-Koseki Y, Toyoda T, Okamura K, et al: The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 450:908–912. 2007. View Article : Google Scholar : PubMed/NCBI
21	Kim JK, Estève PO, Jacobsen SE and Pradhan S: UHRF1 binds G9a and participates in p21 transcriptional regulation in mammalian cells. Nucleic Acids Res. 37:493–505. 2009. View Article : Google Scholar : PubMed/NCBI
22	Jin W, Chen L, Chen Y, Xu SG, Di GH, Yin WJ, Wu J and Shao ZM: UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer. Breast Cancer Res Treat. 123:359–373. 2010. View Article : Google Scholar : PubMed/NCBI
23	Meilinger D, Fellinger K, Bultmann S, Rothbauer U, Bonapace IM, Klinkert WE, Spada F and Leonhardt H: Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO Rep. 10:1259–1264. 2009. View Article : Google Scholar : PubMed/NCBI
24	Abbady AQ, Bronner C, Bathami K, Muller CD, Jeanblanc M, Mathieu E, Klein JP, Candolfi E and Mousli M: TCR pathway involves ICBP90 gene down-regulation via E2F binding sites. Biochem Pharmacol. 70:570–579. 2005. View Article : Google Scholar : PubMed/NCBI
25	Distler P and Holt PR: Are right- and left-sided colon neoplasms distinct tumors? Dig Dis. 15:302–311. 1997. View Article : Google Scholar : PubMed/NCBI
26	Birkenkamp-Demtroder K, Olesen SH, Sørensen FB, et al: Differential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid. Gut. 54:374–384. 2005. View Article : Google Scholar : PubMed/NCBI
27	Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N and Iacopetta B: Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. 355:1745–1750. 2000. View Article : Google Scholar : PubMed/NCBI
28	Kapiteijn E, Liefers GJ, Los LC, et al: Mechanisms of oncogenesis in colon versus rectal cancer. J Pathol. 195:171–178. 2001. View Article : Google Scholar : PubMed/NCBI
29	Fric P, Sovová V, Sloncová E, Lojda Z, Jirásek A and Cermák J: Different expression of some molecular markers in sporadic cancer of the left and right colon. Eur J Cancer Prev. 9:265–268. 2000. View Article : Google Scholar : PubMed/NCBI