Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells

作者：Wu, Guozhen; Wang, Ning; Luo, Ying; Zhang, Yanyan; Wang, Peng; Zhu, Zhengyan; Gao, Yingtang; Du, Zhi^*; Yang, Bin^*

来源：Tumor Biology, 2017, 39(5): 699117.

DOI：10.1177/1010428317699117

• Senescence
• DNA damage response
• 3-deazaneplanocin A
• histone methylation

Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S-adenosylmethionine to S-adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S-adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53-p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling.

• 出版日期2017-5-1
• 单位天津医科大学