Lactate accumulation induces H4K12la to activate super-enhancer-driven RAD23A expression and promote niraparib resistance in ovarian cancer

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-03-19 DOI:10.1186/s12943-025-02295-w

Bingfeng Lu, Shuo Chen, Xue Guan, Xi Chen, Yuping Du, Jing Yuan, Jielin Wang, Qinghua Wu, Lingfeng Zhou, Xiangchun Huang, Yang Zhao

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Abstract

Ovarian cancer is a gynecological malignancy with the highest recurrence and mortality rates. Although niraparib can effectively affect its progression, the challenge of drug resistance remains. Herein, niraparib-resistant ovarian cancer cell lines were constructed to identify the abnormally activated enhancers and associated target genes via RNA in situ conformation sequencing. Notably, the target gene RAD23A was markedly upregulated in niraparib-resistant cells, and inhibiting RAD23A restored their sensitivity. Additionally, abnormal activation of glycolysis in niraparib-resistant cells induced lactate accumulation, which promoted the lactylation of histone H4K12 lysine residues. Correlation analysis showed that key glycolysis enzymes such as pyruvate kinase M and lactate dehydrogenase A were significantly positively correlated with RAD23A expression in ovarian cancer. Additionally, H4K12la activated the super-enhancer (SE) of niraparib and RAD23A expression via MYC transcription factor, thereby enhancing the DNA damage repair ability and promoting the drug resistance of ovarian cancer cells. Overall, the findings of this study indicate that lactic acid accumulation leads to lactylation of histone H4K12la, thereby upregulating SE-mediated abnormal RAD23A expression and promoting niraparib resistance in ovarian cancer cells, suggesting RAD23A as a potential therapeutic target for niraparib-resistant ovarian cancer.

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乳酸积累诱导H4K12la激活超增强剂驱动的RAD23A表达，促进卵巢癌对尼拉帕尼的耐药

卵巢癌是复发率和死亡率最高的妇科恶性肿瘤。尽管尼拉帕尼可以有效地影响其进展，但耐药性的挑战仍然存在。本文构建耐尼拉帕尼卵巢癌细胞系，通过RNA原位构象测序鉴定异常激活的增强子和相关靶基因。值得注意的是，靶基因RAD23A在尼拉帕尼耐药细胞中显著上调，抑制RAD23A可恢复其敏感性。此外，耐尼帕尼细胞中糖酵解的异常激活诱导乳酸积累，从而促进组蛋白H4K12赖氨酸残基的乳酸化。相关分析显示，丙酮酸激酶M、乳酸脱氢酶A等关键糖酵解酶与RAD23A在卵巢癌中的表达呈显著正相关。此外，H4K12la通过MYC转录因子激活niraparib和RAD23A的超级增强子（super-enhancer， SE）表达，从而增强DNA损伤修复能力，促进卵巢癌细胞的耐药。总之，本研究结果表明，乳酸积累导致组蛋白H4K12la乳酸化，从而上调se介导的RAD23A异常表达，促进卵巢癌细胞对尼拉帕尼耐药，提示RAD23A可能是尼拉帕尼耐药卵巢癌的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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