表观遗传可塑性是癌症靶向治疗面临的重要挑战。然而，控制这一过程的分子基础尚未明确界定。尽管PARP抑制剂（PARPi）在癌症治疗中取得了相当成功，但其在肝细胞肝癌（HCC）尤其是有限的响应一直是临床应用的瓶颈。在这里，我们研究了组蛋白甲基转移酶KMT5C在控制PARPi敏感性方面的分子基础，并探讨了增强PARPi疗效的潜在治疗策略。我们发现KMT5C是H4K20的三甲基转移酶，作为一个可靶向的表观遗传因子，它在小鼠的de novo MYC/ Trp53-/-和异位移植瘤肝瘤模型中促进了肝肿瘤的生长。值得注意的是，环境应激诱导的KMT5C表达对DNA修复和HCC细胞存活至关重要。机制上，KMT5C与同源重组修复的关键组分RAD51相互作用，并促进RAD51/RAD54复合物的形成，这对DSBs修复的激活至关重要。这种效应依赖于KMT5C的甲基转移酶活性。我们进一步证明了KMT5C在促进HCC进展中的功能依赖于RAD51。重要的是，KMT5C的药理抑制剂（A196）或基因抑制剂使肝癌细胞对PARPi产生敏感性。KMT5C通过激活DNA修复应答在促进肝癌进展中起到重要作用。我们的结果揭示了一种利用KMT5C抑制剂A196与奥拉帕尼同时应用的新型治疗方法，作为一种潜在的HCC治疗策略。版权所有 © 2023年美国肝病研究学会。

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 PARP inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in hepatocellular carcinoma (HCC), has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy.We identified KMT5C, a tri-methyltransferase 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 DSBs 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.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.Copyright © 2023 American Association for the Study of Liver Diseases.