HuR Reduces Radiation-Induced DNA Damage by Enhancing Expression of ARID1A
HuR Reduces Radiation-Induced DNA Damage by Enhancing Expression of ARID1A
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DOI：
10.3390/cancers11122014
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发表时间：
2019-12-01
期刊：
影响因子：
5.2
通讯作者：
Munshi, Anupama
中科院分区：
文献类型：
--
作者：
Andrade, Daniel;Mehta, Meghna;Munshi, Anupama
肿瘤抑制因子ARID 1A是染色质重塑复合物SWI/SNF的一个亚基，调节细胞周期进程，与肿瘤抑制因子TP 53相互作用，并防止基因组不稳定性。此外，ARID 1A已被证明可以促进对癌症治疗的抵抗。通过促进非同源末端连接（NHEJ），ARID 1A增强DNA修复。因此，ARID 1A已被提出作为使癌细胞对化疗和放疗敏感的有前景的治疗靶点。在这里，我们报告ARID 1A受人类抗原R（HuR）的调节，HuR是一种RNA结合蛋白，在广泛的癌症中高度表达，并能够抵抗化疗和放疗。我们的研究结果表明，HuR结合ARID 1A mRNA，从而增加其在乳腺癌细胞中的稳定性。我们进一步发现，ARID 1A表达抑制辐射引起的DNA双链断裂（DSB）的积累，并可以挽救由HuR抑制引发的辐射抗性的丧失，这表明ARID 1A在HuR驱动的辐射抗性中起着重要作用。总之，我们的工作表明，HuR和ARID 1A形成了辐射抗性的重要调节轴，可以有针对性地改善乳腺癌患者的放射治疗。
Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), ARID1A enhances DNA repair. Consequently, ARID1A has been proposed as a promising therapeutic target to sensitize cancer cells to chemotherapy and radiation. Here, we report that ARID1A is regulated by human antigen R (HuR), an RNA-binding protein that is highly expressed in a wide range of cancers and enables resistance to chemotherapy and radiation. Our results indicate that HuR binds ARID1A mRNA, thereby increasing its stability in breast cancer cells. We further find that ARID1A expression suppresses the accumulation of DNA double-strand breaks (DSBs) caused by radiation and can rescue the loss of radioresistance triggered by HuR inhibition, suggesting that ARID1A plays an important role in HuR-driven resistance to radiation. Taken together, our work shows that HuR and ARID1A form an important regulatory axis in radiation resistance that can be targeted to improve radiotherapy in breast cancer patients.