Jo Yoon Kyung, Park Na Yeon, Shin Ji Hyun, Jo Doo Sin, Bae Ji-Eun, Choi Eun Sun, Maeng Sungho, Jeon Hong Bae, Roh Seon Ae, Chang Jong Wook, Kim Jin Cheon, Cho Dong-Hyung
Department of Gerontology, Graduate School of East-West Medical Science, Kyung Hee University, Seoul, Republic of Korea.
Biomedical Research Institute, MEDIPOST Corporation, Seongnam, Republic of Korea.
Anticancer Res. 2018 Jan;38(1):271-277. doi: 10.21873/anticanres.12218.
The ultraviolent irradiation resistance-associated gene (UVRAG), a component of the Beclin 1/autophagy-related 6 complex, regulates the autophagy initiation step and functions in the DNA-damage response. UVRAG is frequently mutated in various cancer types, and mutations of UVRAG increase sensitivity to chemotherapy by impairing DNA-damage repair. In this study, we addressed the epigenetic regulation of UVRAG in colorectal cancer cells. UVRAG expression was increased in cells treated with histone deacetylase (HDAC) inhibitors, such as valproic acid and suberoylanilide hydroxamic acid. Down-regulation of HDAC1 enhanced UVRAG expression in colorectal cancer cells. In addition, both chemical and genetic inhibition of HDAC1 reduced the activation of caspase-3 and cytotoxicity in 5-fluorouracil (5FU)-treated cancer cells. In contrast, UVRAG overexpression inhibited caspase activation and cell death in 5FU-treated cells. Taken together, our findings suggest that up-regulation of UVRAG by HDAC1 inhibition potentiates DNA-damage-mediated cell death in colorectal cancer cells.
紫外线辐射抗性相关基因（UVRAG）是Beclin 1/自噬相关蛋白6复合物的一个组成部分，它调节自噬起始步骤并在DNA损伤反应中发挥作用。UVRAG在多种癌症类型中经常发生突变，并且UVRAG的突变会通过损害DNA损伤修复而增加对化疗的敏感性。在本研究中，我们探讨了结直肠癌细胞中UVRAG的表观遗传调控。在用组蛋白去乙酰化酶（HDAC）抑制剂（如丙戊酸和辛二酰苯胺异羟肟酸）处理的细胞中，UVRAG表达增加。HDAC1的下调增强了结直肠癌细胞中UVRAG的表达。此外，HDAC1的化学抑制和基因抑制均降低了5-氟尿嘧啶（5FU）处理的癌细胞中caspase-3的激活和细胞毒性。相反，UVRAG过表达抑制了5FU处理细胞中的caspase激活和细胞死亡。综上所述，我们的研究结果表明，HDAC1抑制导致的UVRAG上调增强了结直肠癌细胞中DNA损伤介导的细胞死亡。
Zotero 插件