Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

J Exp Clin Cancer Res. 2016 Nov 14;35(1):174. doi: 10.1186/s13046-016-0453-5.

Mahmoud Alhosin ¹ ² ³ ⁴, Ziad Omran ⁵, Mazin A Zamzami ⁶ ⁷ ⁸, Abdulrahman L Al-Malki ⁶ ⁷, Hani Choudhry ⁶ ⁷ ⁸ ⁹, Marc Mousli ¹⁰, Christian Bronner ¹¹

Affiliations

1 Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. [email protected].
2 Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. [email protected].
3 Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. [email protected].
4 Biochemistry Department, Faculty of Sciences, Cancer and Mutagenesis Unit, King Fahd Centre for Medical Research, King Abdulaziz University, P. O. Box 80203, Jeddah, 21589, Saudi Arabia. [email protected].
5 College of Pharmacy, Umm Al-Qura University, 21955, Makkah, Kingdom of Saudi Arabia.
6 Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
7 Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
8 Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
9 Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
10 Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, Université de Strasbourg, Faculté de pharmacie, 74 route du Rhin, 67401, Illkirch, France.
11 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964 CNRS UMR 7104, Université de Strasbourg, 1 rue Laurent Fries, 67404, Illkirch, France. [email protected].

PMID: 27839516 DOI: 10.1186/s13046-016-0453-5

Abstract

Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of Cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 ^INK4A , BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows Cancer cells to escape Apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several Enzymes including histone deacetylase 1 (HDAC1), DNA Methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for Cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in Cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent Apoptosis.

Keywords

DNA methylation; Epigenetic; Tumor suppressor genes; UHRF1; p16INK4A; p53; p73.

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