在K23/K36处的S100A8乳酸化减少了RNF5-依赖性降解并促进结直肠癌癌症的进展
S100A8 lactylation at K23/K36 reduces RNF5-dependent degradation and promotes colorectal cancer progression.
摘要(中文译文)
结直肠癌（CRC）的进展深受酸性、富含乳酸的肿瘤微环境影响。尽管钙结合蛋白S100A8是CRC中已知的致癌驱动因子和预后生物标志物，但其蛋白质稳定性调控机制尚未完全阐明。本研究探讨了乳酸诱导的乳酰化与RNF5介导的S100A8泛素化之间的竞争性相互作用。对临床乳酰化组数据集的再分析和生存分析显示，S100A8在结肠癌组织中高度乳酰化，其表达升高与患者不良预后相关。通过在HCT116和HT-29结肠癌细胞中进行免疫沉淀和突变研究，本研究确定了赖氨酸残基K23和K36为S100A8的主要乳酰化位点。乳酸刺激显著增强了S100A8乳酰化，从而提高了其蛋白质稳定性。在机制上，K23和K36位点的乳酰化破坏了S100A8与E3泛素连接酶RNF5之间的相互作用，从而抑制了RNF5介导的泛素化及随后的蛋白酶体降解。为验证这一交互作用，研究构建了S100A8 K23R/K36R突变体。该突变体通过逃避泛素化表现出增强的内在稳定性，强效促进CRC细胞增殖，并在体外和小鼠异种移植模型中有效逆转了RNF5的抑瘤效应。总之，本研究结果揭示了一种新的代谢-翻译后修饰交互作用，即肿瘤来源的乳酸通过乳酰化稳定S100A8，使其免受RNF5介导的降解，最终驱动CRC发病。
Abstract
Colorectal cancer (CRC) progression is deeply influenced by the acidic, lactate-rich tumor microenvironment. While the calcium-binding protein S100A8 is a known oncogenic driver and prognostic biomarker in CRC, the mechanisms governing its protein stability remain incompletely understood. This study investigated the competitive interplay between lactate-induced lactylation and RNF5-mediated ubiquitination of S100A8. Reanalysis of clinical lactylomic datasets and survival analyses revealed that S100A8 is heavily lactylated in colon cancer tissues and its elevated expression correlates with poor patient prognosis. Through immunoprecipitation and mutagenesis studies in HCT116 and HT-29 colon cancer cells, this study identified lysine residues K23 and K36 as the primary lactylation sites on S100A8. Lactate stimulation significantly enhanced S100A8 lactylation, which consequently increased its protein stability. Mechanistically, lactylation at K23 and K36 impaired the interaction between S100A8 and the E3 ubiquitin ligase RNF5, thereby suppressing RNF5-mediated ubiquitination and subsequent proteasomal degradation. To validate this crosstalk, an S100A8 K23R/K36R mutant was generated. This mutant exhibited enhanced intrinsic stability by evading ubiquitination, robustly promoted CRC cell proliferation, and effectively reversed the tumor-suppressive effects of RNF5 both in vitro and in murine xenograft models. Collectively, findings of this study uncover a novel metabolic-post-translational modification crosstalk in which tumor-derived lactate stabilizes S100A8 via lactylation, shielding it from RNF5-mediated degradation and ultimately driving CRC pathogenesis.
如何引用
AMA
Hu-Cheng Yan, Xin-Xi Lai, Yan Liu, Lei-Ming Sheng. S100A8 lactylation at K23/K36 reduces RNF5-dependent degradation and promotes colorectal cancer progression.. Biochemical and biophysical research communications. 2026; doi:10.1016/j.bbrc.2026.153827.
APA
Hu-Cheng Yan, Xin-Xi Lai, Yan Liu, Lei-Ming Sheng (2026). S100A8 lactylation at K23/K36 reduces RNF5-dependent degradation and promotes colorectal cancer progression.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.153827
GB/T 7714
Hu-Cheng Yan, Xin-Xi Lai, Yan Liu, Lei-Ming Sheng. S100A8 lactylation at K23/K36 reduces RNF5-dependent degradation and promotes colorectal cancer progression.[J]. Biochemical and biophysical research communications, 2026 doi:10.1016/j.bbrc.2026.153827.
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