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Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage.

ABSTRACT: Polycomb protein histone methyltransferase enhancer of Zeste homologe 2 (EZH2) is frequently overexpressed in human malignancy and is implicated in cancer cell proliferation and invasion. However, it is largely unknown whether EZH2 has a role in modulating DNA damage response. Here, we show that EZH2 is an important determinant of cell fate decision in response to genotoxic stress. EZH2 depletion results in abrogation of both cell cycle G1 and G2/M checkpoints, directing DNA damage response toward predominant apoptosis in both p53-proficient and p53-deficient cancer cells, but not in normal cells. Mechanistically, EZH2 regulates DNA damage response in p53 wild-type cells mainly through transcriptional repression of FBXO32, which binds to and directs p21 for proteasome-mediated degradation, whereas it affects p53-deficient cells through regulating Chk1 activation by a distinct mechanism. Furthermore, pharmacological depletion of EZH2 phenocopies the effects of EZH2 knockdown on cell cycle checkpoints and apoptosis. These data unravel a crucial role of EZH2 in determining the cancer cell outcome following DNA damage and suggest that therapeutic targeting oncogenic EZH2 might serve as a strategy for improving conventional chemotherapy in a given malignancy.

SUBMITTER: Wu Z

PROVIDER: S-EPMC3190113 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage.

Wu Z Z Lee S T ST Qiao Y Y Li Z Z Lee P L PL Lee Y J YJ Jiang X X Tan J J Aau M M Lim C Z H CZ Yu Q Q Yu Q Q

Cell death and differentiation 20110506 11

Polycomb protein histone methyltransferase enhancer of Zeste homologe 2 (EZH2) is frequently overexpressed in human malignancy and is implicated in cancer cell proliferation and invasion. However, it is largely unknown whether EZH2 has a role in modulating DNA damage response. Here, we show that EZH2 is an important determinant of cell fate decision in response to genotoxic stress. EZH2 depletion results in abrogation of both cell cycle G1 and G2/M checkpoints, directing DNA damage response towa ...[more]

PMID: 21546904

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Project description:BackgroundLack of understanding of the response of hepatocellular carcinoma (HCC) to anticancer drugs causes the high mortality of HCC patients. Bleomycin (BLM) that induces DNA damage is clinically used for cancer therapy, while the mechanism underlying BLM-induced DNA damage response (DDR) in HCC cells remains ambiguous. Given that 14-3-3 proteins are broadly involved in regulation of diverse biological processes (BPs)/pathways, we investigate how a 14-3-3 isoform coordinates particular BPs/pathways in BLM-induced DDR in HCC.Methodology/principal findingsUsing dual-tagging quantitative proteomic approach, we dissected the 14-3-3? interactome formed during BLM-induced DDR, which revealed that 14-3-3? via its associations with multiple pathway-specific proteins coordinates multiple pathways including chromosome remodeling, DNA/RNA binding/processing, DNA repair, protein ubiquitination/degradation, cell cycle arrest, signal transduction and apoptosis. Further, "zoom-in" investigation of the 14-3-3? interacting network indicated that the BLM-induced interaction between 14-3-3? and a MAP kinase TAK1 plays a critical role in determining cell propensity of apoptosis. Functional characterization of this interaction further revealed that BLM triggers site-specific phosphorylations in the kinase domain of TAK1. These BLM-induced changes of phosphorylations directly correlate to the strength of the TAK1 binding to 14-3-3?, which govern the phosphorylation-dependent TAK1 activation. The enhanced 14-3-3?-TAK1 association then inhibits the anti-apoptotic activity of TAK1, which ultimately promotes BLM-induced apoptosis in HCC cells. In a data-dependent manner, we then derived a mechanistic model where 14-3-3? plays the pivotal role in integrating diverse biological pathways for cellular DDR to BLM in HCC.ConclusionsOur data demonstrated on a systems view that 14-3-3? coordinates multiple biological pathways involved in BLM-induced DDR in HCC cells. Specifically, 14-3-3? associates with TAK1 in a phosphorylation-dependent manner to determine the cell fate of BLM-treated HCC cells. Not only individual proteins but also those critical links in the network could be the potential targets for BLM-mediated therapeutic intervention of HCC.

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Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage.

Publications

Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage.

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