Epigenetic Control of Cisplatin Resistance: Focus on Cited2 Selected Histone Acetylation and P53 in Regulation of Dna Repair Genes and Apoptosis

  • Chao, Chuck C.-K. (PI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Cisplatin, widely used in anticancer therapy is limited by the development of drug resistance. The specific genes responsible for the resistance are starting to be identified. Using a genomewide analysis, we have initially identified nine “chemoresistance genes” candidate genes and characterized their role in drug response. Interestingly, these genes were transiently upregulated by p53 at low resistance stage, and loss high expression level without drug stress, suggesting involvement of dynamic chromatin conformation or epigenetic regulation. Furthermore, silencing expression of CITED2 (a coregulator of p300 acetyltransferase), one of the most prominant cisplatin resistance genes, resulted in dramatic accumulation of DNA double strand break (DSB) and sensitization of cancer cells to cisplatin, but not to mitotoxic taxol. We hypothesize that expression of DNA repair genes is regulated by CITED2-associated chromatin relaxation and p53 transactivation, and DSB level is critical for drug sensitivity. However, the underlying mechanism is completely unknown. PiwiI2, a member of the PIWI gene family, is initially known to express in germ line stem cells of testis in normal adults, and is later found widely expressed in various types of tumors. It has also been reported that PIWIL2 inhibits apoptosis and stimulates proliferation through activation of Stat3/Bcl-XL pathway. Notably, PIWIL2 also regulates p300 acetyltransferase activity and chromatin remodeling in various organisms. The expression of DNA repair genes and DSB repair may be regulated by PIWI2. We hypothesize that PIWI2 plays a critical, novel role in cisplatin sensitivity/resistance. In this study, we hypothesize that DNA repair genes are regulated by CITED2 and PIWIL2 -mediated chromatin relaxation and transactivator p53 in DSB level-dependent manner, and that failure of this response leads to DSB accumulation and activation of apoptotic gene (such as Bax) leading to apoptosis of cancer cells. The underlying mechanism and biological significance will be elucidated here. The biological significance of anticipated genes will be characterized by knockdown expression using RNA interference (RNAi) and ectopic expression in cell viability assay in cancer cells and cell-derived xerograft tumors. For gene regulation, kinase signals, modification of p53 and epigenetic factors, and components and their interaction in preference of DNA repair genes and apoptotic gene (focusing on Bax) will be investigated in detail using basic molecular biology and cell biology techniques. In this proposal (three-year studies), we will emphasize the following topics. First, CITED2-mediated epigenetic regulation, focusing on histone modification by histone acetyl transferase p300 and GCN5, of DNA repair genes (ERCC1 and RAD5J), in interaction with p53, in cisplatin resistance. Second, PIWIL2-mediated epigenetic regulation of DNA repair genes (ERCC1 and RAD51) and its significance in p53-regulated cisplatin resistance. Third, Elucidation of p53 based components (Hzf and Cas) in preference of targeting DNA repair genes (ERCC1 and RAD51) and apoptotic Bax gene following cisplatin stress. Uncovering of these areas, which have not been investigated, will shed light on the understanding of basics in cisplatin resistance at genetic and epigenetic levels, in hope that purposed DSB accumulation using this finding may be a novel target for cancer therapy.

Project IDs

Project ID:PC10507-0666
External Project ID:MOST105-2320-B182-036
StatusFinished
Effective start/end date01/08/1631/07/17

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