Department of Biochemistry, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore (NUS), Singapore 117596, Singapore; NUS Center for Cancer Research, YLLSOM, NUS, Singapore 117599, Singapore.
Department of Radiation Oncology, National University Hospital (NUH), Singapore 119074, Singapore; National University Cancer Institute, Singapore National University Health System (NUHS), Singapore 119074, Singapore.
Cell Rep. 2021 Aug 31;36(9):109621. doi: 10.1016/j.celrep.2021.109621.
Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.
放射治疗（RT）抵抗是癌症治疗失败的主要原因，这些癌症将确定性 RT 作为其主要治疗方式。本研究确定癌症/睾丸（CT）抗原 G 抗原（GAGE）是宫颈癌放射抵抗的介质。在临床样本中，GAGE 表达水平升高与新出现的 RT 抵抗呈正相关。GAGE，特别是 GAGE12 蛋白变体，通过 synemin 依赖性染色质定位赋予 RT 抵抗性，促进组蛋白去乙酰化酶 1/2（HDAC1/2）与其抑制剂肌动蛋白的结合。这导致组蛋白 3 赖氨酸 56 乙酰化（H3K56Ac）水平升高、染色质可及性增加和 DNA 修复效率提高。GAGE 相关复合物的分子或药理学破坏可恢复放射敏感性。从分子水平上看，本研究证明了 GAGE 在调节染色质动力学中的作用。从临床角度来看，本研究提出了将 GAGE 作为初始诊断时识别不良反应者的预筛选生物标志物的效用，以及靶向 GAGE 及其相关复合物并与放射治疗联合使用以改善治疗效果的潜在治疗方法。
