H3K18la通过激活IGF2BP1-COX2信号通路促进鼻咽癌进展

文献信息

中文摘要

鼻咽癌（NPC）是起源于鼻咽上皮黏膜的恶性肿瘤，其发生发展与代谢重编程密切相关。乳酸化是一种由乳酸诱导的表观遗传修饰，在基因转录中发挥调控作用。H3K18la在NPC恶性进展中的确切功能和机制尚待阐明。本研究表明，NPC组织中糖酵解通路显著激活，并伴随H3K18la表达升高，且其与肿瘤分期呈正相关。后续研究表明，由乳酸脱氢酶A（LDHA）介导的乳酸生成促进了H3K18la修饰。抑制LDHA可特异性导致H3K18la水平降低、NPC细胞增殖受抑以及凋亡增加。H3K18la上调RNA结合蛋白IGF2BP1，而抑制LDHA或IGF2BP1会降低COX2 mRNA稳定性和表达，从而影响NPC细胞增殖和凋亡抵抗。总之，本研究表明H3K18la修饰通过激活IGF2BP1-COX2信号通路对NPC恶性进展至关重要。该研究阐明了NPC中的乳酸化修饰机制，为其治疗提供了新的靶点。

英文摘要

Nasopharyngeal carcinoma (NPC) is a malignant tumor arising from the nasopharyngeal epithelial mucosa, with its development closely associated with metabolic reprogramming. Lactylation, an epigenetic modification induced by lactate, plays a regulatory role in gene transcription.The precise function and mechanisms of H3K18la in NPC malignancy progression are yet to be clarified.This study demonstrates that the glycolytic pathway is markedly activated in NPC tissues, accompanied by elevated expression of H3K18la, which positively correlates with tumour stage. Subsequent studies showed that lactic acid production, mediated by lactate dehydrogenase A (LDHA), facilitates H3K18la modification. Inhibiting LDHA specifically leads to reduced H3K18la levels, suppressed proliferation of NPC cells, and increased apoptosis.H3K18la upregulates the RNA-binding protein IGF2BP1, while inhibiting LDHA or IGF2BP1 reduces COX2 mRNA stability and expression, influencing NPC cell proliferation and apoptosis resistance. In summary, this study indicates that H3K18la modification is crucial for NPC malignancy through the activation of the IGF2BP1-COX2 signaling pathway. This research elucidates lactylation modification mechanisms in NPC, presenting novel targets for its treatment.