H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer.
H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer.
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DOI：
10.1073/pnas.2114324119
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发表时间：
2022-05-24
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
这项研究表明，抗雄激素治疗诱导的病毒模拟反应是至关重要的抗肿瘤活性。H3 K9三甲基化以沉默内源性重复元件对于在前列腺癌中恢复异染色质稳定性和进展为抗雄激素抗性是必不可少的。我们发现H3 K9三甲基化机制与前列腺癌男性的不良结局有关。阻断这一表观遗传轴可以使耐药肿瘤重新敏感并引起细胞毒性干扰素反应。抗雄激素时机和H3 K9甲基化-内源性重复元件-干扰素轴的调节应被考虑在前列腺癌的新型表观遗传疗法和免疫策略的发展中。抗雄激素策略仍然是前列腺癌治疗的支柱，但耐药性的发展。我们表明，雄激素阻断前列腺癌导致去阻遏的retroelements（RE），其次是双链RNA（dsRNA）刺激的干扰素反应，阻断肿瘤的生长。正向遗传学方法鉴定H3 K9三甲基化（H3 K9 me 3）为对抗雄激素的基本表观遗传适应，其使RE的转录沉默成为可能，否则RE刺激干扰素信号传导和糖皮质激素受体表达。终末H3 K9 me 3编写者的表达升高与患者激素治疗结果不良相关。强制表达H3 K9 me 3作家赋予阻力，而抑制H3 K9-三甲基化作家和读者恢复RE表达，阻断抗雄激素抗性。我们的工作揭示了一个耐药轴，整合了多种细胞信号传导元件，并确定了潜在的药理学漏洞。
This study reveals that antiandrogen therapy induces viral mimicry responses that are crucial for antitumor activity. H3K9 trimethylation to silence endogenous repeat elements is essential for regaining heterochromatin stability and progression to antiandrogen resistance in prostate cancer. We found that the H3K9 trimethylation machinery is linked to poor outcomes in men with prostate cancer. Blockade of this epigenetic axis can resensitize drug-resistant tumors and elicit cytotoxic interferon responses. Antiandrogen timing and regulation of the H3K9 methylation–endogenous repeat elements– interferon axis should be considered in the development of novel epigenetic therapies and immunotherapeutic strategies for prostate cancer. Antiandrogen strategies remain the prostate cancer treatment backbone, but drug resistance develops. We show that androgen blockade in prostate cancer leads to derepression of retroelements (REs) followed by a double-stranded RNA (dsRNA)-stimulated interferon response that blocks tumor growth. A forward genetic approach identified H3K9 trimethylation (H3K9me3) as an essential epigenetic adaptation to antiandrogens, which enabled transcriptional silencing of REs that otherwise stimulate interferon signaling and glucocorticoid receptor expression. Elevated expression of terminal H3K9me3 writers was associated with poor patient hormonal therapy outcomes. Forced expression of H3K9me3 writers conferred resistance, whereas inhibiting H3K9-trimethylation writers and readers restored RE expression, blocking antiandrogen resistance. Our work reveals a drug resistance axis that integrates multiple cellular signaling elements and identifies potential pharmacologic vulnerabilities.
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