SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair

IF 5.9 2区 医学 Q1 ONCOLOGY
Yujia Huang, Ming Tang, Zhiyi Hu, Bailian Cai, Guofang Chen, Lijun Jiang, Yan Xia, Pujun Guan, Xiaoqi Li, Zhiyong Mao, Xiaoping Wan, Wen Lu
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Abstract

Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems.

Abstract Image

SMYD3 在非同源末端连接修复中通过对 LIG4/XRCC4/XLF 复合物的表观遗传调控促进子宫内膜癌的发生
子宫内膜癌(EC)是影响女性生殖道的最常见恶性肿瘤之一,其发病率在全球范围内迅速飙升。尽管组蛋白甲基转移酶SMYD3与多种癌症的发生和发展有密切关系,但它在子宫内膜癌中的具体致癌作用仍未得到研究。在本研究中,我们发现 SMYD3 在子宫内膜癌样本中的表达水平显著上调,并与子宫内膜癌的进展相关。通过细致的体内和体外实验,我们发现SMYD3的消耗会抑制细胞的增殖、迁移和侵袭能力,导致非同源末端连接修复(NHEJ)受损,并提高EC细胞对辐射的敏感性。此外,我们的通路富集分析强调了DNA损伤修复通路在调控EC进展中的关键作用。从机理上讲,在对 DNA 损伤做出反应时,SMYD3 会以 PARP1 依赖性方式被招募到这些位点,特别是甲基化 LIG4。这种甲基化引发了 LIG4/XRCC4/XLF 复合物的依次组装,积极参与 NHEJ 通路,从而促进心肌梗死的进展。值得注意的是,我们的研究结果突显了 SMYD3 在 NHEJ 修复中的重要作用及其与心肌梗死进展的直接相关性。耐人寻味的是,用特异性抑制剂 BCI-121 对 SMYD3 进行药物干预是一种有效的策略,它能明显抑制癌细胞的致瘤性,并显著提高放疗的疗效。总之,我们的综合数据将 SMYD3 定位为 NHEJ 修复的核心因子,并通过体外和体内系统验证了其作为子宫内膜癌治疗药物靶点的潜力。
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来源期刊
Oncogenesis
Oncogenesis ONCOLOGY-
CiteScore
11.90
自引率
0.00%
发文量
70
审稿时长
26 weeks
期刊介绍: Oncogenesis is a peer-reviewed open access online journal that publishes full-length papers, reviews, and short communications exploring the molecular basis of cancer and related phenomena. It seeks to promote diverse and integrated areas of molecular biology, cell biology, oncology, and genetics.
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