The Role of Polycomb Group Protein EZH2 in Cancer Progression.

Polycomb;EZH2;Cancer;Pathology;Health Sciences;Pathology

Cao, QiVarani, James ;

University of Michigan

关键词: Polycomb;    EZH2;    Cancer;    Pathology;    Health Sciences;    Pathology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/60769/qcao_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Chair: Arul M. Chinnaiyan The Polycomb group and the Trithorax group proteins are part of the cellular memory system that maintains cellular identity during development and differentiation. Byregulating histone modification and DNA methylation, Polycomb group and trithorax group proteins affect a wide range of cellular process that include apoptosis, proliferation, differentiation, cell cycle regulation and tumorigenesis. There are multiple lines of evidence suggesting that Polycomb group proteins are dysregulated in cancer and may promote cancer progression. We, and others, have demonstrated that EZH2, a Polycomb repressive complex 2 protein with histone methyltransferase activity, is dysregulated in prostate, breast, lung, liver and many other types of carcinomas.In the present study, we identified EZH2 as a biomarker of aggressive breast cancer. Overexpression of EZH2 is associated with poor patient prognosis. We recapitulated this observation in in vitro cell culture models by overexpressing EZH2 and characterized its biological function.EZH2 overexpression enhances histone deacetylase (HDAC) activity and promotes cell anchorage-independent growth and invasiveness.Inhibitors of HDAC were able to abolish these effects of EZH2. In addition, we identified E-cadherin, a well known tumor suppressor gene, as a target of EZH2.Our studies revealed a novel mechanism, where transcriptional regulation of E-Cadherin by EZH2 was essential for EZH2 mediated cell invasion and cancer progression. Our efforts to address the dysregulation of EZH2 in cancer, identified a microRNA, hsa-miR-101, as a regulator of EZH2 expression that could repress EZH2 expression both at transcript and protein levels. Overexpression of hsa-miR-101 inhibits tumor formation. Most importantly, when we queried array comparative genomic hybridization (aCGH) datasets, a significant number of metastatic prostate and breast cancer samples, showed genomic deletion or loss of heterozygosity of the region that harbors hsa-miR-101-1. Furthermore, quantitative PCR of the genomic DNA confirmed the deletion or loss of heterozygosity of miR101-1. EZH2 was overexpressed in the samples with this aberration, outlining a possible mechanism of EZH2 dysregulation observed in cancer. Taken together, my thesis study identified EZH2 as a prognostic biomarker of breast cancer and revealed the underlying mechanisms for its up-regulation in cancer as well as its oncogenic function.