2020年10月21日出版的《自然》杂志在线发表了加拿大多伦多大学健康网络Daniel D. De Carvalho、Parinaz Mehdipour研究组的最新研究成果。他们发现表观遗传疗法诱导SINE反向转录和ADAR1依赖。

为了找到可以与病毒模拟反应协同作用的靶点，研究人员尝试确定由表观遗传疗法激活的免疫原性逆转录元件。

研究人员发现内含子和基因间的SINE元件，特别是反向重复Alus序列，是由药物诱导免疫原性dsRNA的主要来源。这些反向重复Alus通常位于“孤儿” CpG岛的下游。在哺乳动物中，靶向ADAR1酶并破坏反向重复Alu dsRNA序列阻碍了MDA5受体的激活。研究发现ADAR1建立了负反馈回路，从而限制了病毒模拟表观遗传疗法的功效。

在患者来源癌细胞中ADAR1的缺失增强了表观遗传疗法的功效，抑制了肿瘤的生长并减少了癌症的发生。因此，表观遗传疗法通过诱导反向重复基因Alus序列从而形成病毒模仿环境，这形成对ADAR1的依赖性。该研究发现表明，表观遗传疗法结合ADAR1抑制剂代表了一种潜在的癌症治疗策略。

据悉，靶向表观遗传抑制因子的癌症疗法通过激活人基因组中的逆转录元件来发挥功能。逆转录产物可以形成激活MDA5模式识别受体的双链RNA（dsRNA）。病毒模仿状态导致癌细胞适应性丧失，并刺激先天和适应性免疫反应。然而，表观遗传疗法在临床上的疗效受到诸多限制。

附：英文原文

Title: Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Author: Parinaz Mehdipour, Sajid A. Marhon, Ilias Ettayebi, Ankur Chakravarthy, Amir Hosseini, Yadong Wang, Fabola Atti de Castro, Helen Loo Yau, Charles Ishak, Sagi Abelson, Catherine A. OBrien, Daniel D. De Carvalho

Issue&Volume: 2020-10-21

Abstract: Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor1,2,3,4,5,6. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses7,8. However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of ‘orphan’ CpG islands9. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA10, which prevents activation of the MDA5 receptor11. We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment.

DOI: 10.1038/s41586-020-2844-1

Source: https://www.nature.com/articles/s41586-020-2844-1