<br>组蛋白甲基转移酶 KMT5C 驱动肝癌进展并指导对 PARP 抑制剂的治疗反应。,Hepatology

当前位置： X-MOL 学术 › Hepatology › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

组蛋白甲基转移酶 KMT5C 驱动肝癌进展并指导对 PARP 抑制剂的治疗反应。
Hepatology ( IF 12.9 ) Pub Date : 2023-08-09 , DOI: 10.1097/hep.0000000000000559
Yu Tong ₁ , Fan Wang ₁ , Songling Li ₂ , Wenyun Guo ₁ , Qianyu Li ₁ , Yifei Qian ₁ , Linfeng Li ₁ , Huifang Zhao ₁ , Yonglong Zhang ₃ , Wei-Qiang Gao _{1,

2} , Yanfeng Liu _{1,

4}

Affiliation

背景和目的表观遗传可塑性是癌症靶向治疗的主要挑战。然而，控制这一过程的分子基础尚未明确定义。尽管聚（ADP-核糖）聚合酶抑制剂（PARPi）在癌症治疗中取得了相当大的成功，但对 PARPi 的有限反应，尤其是在 HCC 中，一直是其临床意义的瓶颈。在此，我们研究了控制 PARPi 敏感性的组蛋白甲基转移酶 KMT5C（赖氨酸甲基转移酶 5C）的分子基础，并探索了增强 PARPi 功效的潜在治疗策略。方法和结果我们确定 KMT5C（H4K20 的一种三甲基转移酶）是一种可靶向的表观遗传因子，可促进小鼠从头 MYC/Trp53-/- 和异种移植肝肿瘤模型中的肝肿瘤生长。值得注意的是，环境应激诱导 KMT5C 对于 DNA 修复和 HCC 细胞存活至关重要。从机制上讲，KMT5C 与同源重组修复的关键成分 RAD51 相互作用，并促进 RAD51/RAD54 复合物的形成，这对于激活 dsDNA 断裂修复至关重要。这种效果取决于 KMT5C 的甲基转移酶活性。我们进一步证明KMT5C促进HCC进展的功能依赖于RAD51。重要的是，药物抑制剂 (A196) 或 KMT5C 的基因抑制均可使肝癌细胞对 PARPi 敏感。结论 KMT5C 通过激活 DNA 修复反应在促进肝癌进展中发挥着至关重要的作用。我们的结果揭示了一种使用 KMT5C 抑制剂 A196 与奥拉帕尼同时使用的新治疗方法，作为一种潜在的 HCC 疗法。

"点击查看英文标题和摘要"

Histone methyltransferase KMT5C drives liver cancer progression and directs therapeutic response to PARP inhibitors.

BACKGROUND AND AIMS Epigenetic plasticity is a major challenge in cancer-targeted therapy. However, the molecular basis governing this process has not yet been clearly defined. Despite the considerable success of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in HCC, has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C (lysine methyltransferase 5C) that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy. APPROACH AND RESULTS We identified KMT5C, a trimethyltransferase of H4K20, as a targetable epigenetic factor that promoted liver tumor growth in mouse de novo MYC/Trp53-/- and xenograft liver tumor models. Notably, induction of KMT5C by environmental stress was crucial for DNA repair and HCC cell survival. Mechanistically, KMT5C interacted with the pivotal component of homologous recombination repair, RAD51, and promoted RAD51/RAD54 complex formation, which was essential for the activation of dsDNA breaks repair. This effect depended on the methyltransferase activity of KMT5C. We further demonstrated that the function of KMT5C in promoting HCC progression was dependent on RAD51. Importantly, either a pharmacological inhibitor (A196) or genetic inhibition of KMT5C sensitized liver cancer cells to PARPi. CONCLUSIONS KMT5C played a vital role in promoting liver cancer progression by activating the DNA repair response. Our results revealed a novel therapeutic approach using the KMT5C inhibitor A196, concurrent with olaparib, as a potential HCC therapy.

更新日期：2023-08-09

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南