Zhou Zheng, He Chao, Wang Xumeng, Jin Xinguang, Wen Liping, Yang Yan, Zhou Quan, Wang Weibin, Teng Lisong
Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Int J Biol Sci. 2025 Oct 1;21(14):6373-6388. doi: 10.7150/ijbs.120277. eCollection 2025.
Papillary thyroid carcinoma (PTC) remains among the most prevalent endocrine malignancies globally, with its incidence steadily rising. Although clinical outcomes are generally favorable, a clinically significant subset of patients exhibits highly aggressive tumor phenotypes, characterized by larger tumor size and increased lymph node metastasis. Accumulating evidence implicates metabolic reprogramming and epigenetic dysregulation as pivotal drivers of tumor progression. Lactate, one of the byproducts of tumor metabolism, has recently garnered attention for its regulatory functions beyond metabolism. Histone lactylation, a recently identified epigenetic modification dynamically regulated by intracellular lactate accumulation, has emerged as an important regulator of tumor proliferation, metastasis, immune evasion, and therapeutic resistance. However, the functional implications and mechanistic underpinnings of histone lactylation in PTC remain largely unexplored. Here, we report significantly elevated pan-lysine lactylation and histone H3 lysine 18 lactylation (H3K18la) levels in clinical PTC specimens, with tumor tissues exhibiting markedly higher levels compared to adjacent normal thyroid tissues., correlating positively with aggressive clinicopathological features. Relevant cellular phenotypic assays further support this conclusion. Mechanistically, we demonstrate that H3K18la modification directly facilitates the transcriptional activation of Signal Transducer and Activator of Transcription 1 (STAT1). Activated STAT1 subsequently promotes transcriptional upregulation of Lactate Dehydrogenase A (LDHA), thereby enhancing lactate biosynthesis and establishing a self-perpetuating positive feedback loop. Consequently, tumor-derived lactate orchestrates and sustains malignant progression in PTC through this "H3K18la-STAT1-LDHA" regulatory axis. Collectively, our findings uncover a novel mechanistic linkage between tumor metabolism and epigenetic regulation in PTC, providing critical insights into thyroid cancer pathogenesis. Furthermore, therapeutic targeting of the H3K18la-STAT1-LDHA axis may represent an innovative and promising strategy to improve outcomes for patients with aggressive and refractory PTC.
甲状腺乳头状癌（PTC）仍是全球最常见的内分泌恶性肿瘤之一，其发病率在稳步上升。尽管临床结果总体良好，但有一部分具有临床意义的患者表现出高度侵袭性的肿瘤表型，其特征是肿瘤体积较大且淋巴结转移增加。越来越多的证据表明，代谢重编程和表观遗传失调是肿瘤进展的关键驱动因素。乳酸作为肿瘤代谢的副产物之一，最近因其在代谢以外的调节功能而受到关注。组蛋白乳酸化是一种最近发现的表观遗传修饰，受细胞内乳酸积累的动态调节，已成为肿瘤增殖、转移、免疫逃逸和治疗耐药性的重要调节因子。然而，组蛋白乳酸化在PTC中的功能影响和机制基础在很大程度上仍未被探索。在此，我们报告临床PTC标本中泛赖氨酸乳酸化和组蛋白H3赖氨酸18乳酸化（H3K18la）水平显著升高，肿瘤组织的水平明显高于相邻的正常甲状腺组织，且与侵袭性临床病理特征呈正相关。相关的细胞表型分析进一步支持了这一结论。机制上，我们证明H3K18la修饰直接促进信号转导和转录激活因子1（STAT1）的转录激活。激活的STAT1随后促进乳酸脱氢酶A（LDHA）的转录上调，从而增强乳酸生物合成并建立一个自我维持的正反馈回路。因此，肿瘤来源的乳酸通过这个“H3K18la-STAT1-LDHA”调节轴协调并维持PTC中的恶性进展。总的来说，我们的研究结果揭示了PTC中肿瘤代谢与表观遗传调控之间一种新的机制联系，为甲状腺癌的发病机制提供了关键见解。此外，针对H3K18la-STAT1-LDHA轴的治疗靶向可能代表一种创新且有前景的策略，以改善侵袭性和难治性PTC患者的预后。
