组蛋白乳酰化增强的AURKB通过抑制HNRNPM介导的PSAT1 mRNA降解促进结直肠癌进展。

Histone lactylation-boosted AURKB facilitates colorectal cancer progression by inhibiting HNRNPM-mediated PSAT1 mRNA degradation.

作者信息

Li Yuyi, Peng Jinjin, Wu Di, Xie Qingxin, Hou Yichao, Li Linjing, Zhang Xintian, Liang Yu, Feng Jing, Chen Jiaqing, Chen Wangshuang, Xu Che, Yao Han, Meng Xiangjun

机构信息

Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, China.

出版信息

J Exp Clin Cancer Res. 2025 Aug 11;44(1):233. doi: 10.1186/s13046-025-03498-1.

DOI:10.1186/s13046-025-03498-1

PMID:40784984

Abstract

BACKGROUND

Aurora kinase B (AURKB), a key regulator of mitosis, is frequently upregulated in various malignancies, including colorectal cancer (CRC), and is associated with poor prognosis. However, the limited clinical efficacy of AURKB inhibitors suggests the existence of previously unrecognized oncogenic mechanisms that merit further investigation.

METHODS

AURKB was prioritized through bioinformatic analysis, and its elevated expression in CRC was validated via single-cell RNA sequencing (scRNA-seq) and western blot. The transcriptional activation of AURKB was attributed to H3K18 lactylation, as confirmed by chromatin immunoprecipitation (ChIP)-qPCR. RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA) were conducted to pinpoint the downstream targets of AURKB. The role of the AURKB/phosphoserine aminotransferase 1 (PSAT1) axis in CRC was further studied using both in vitro and in vivo functional experiments. Mass spectrometry, co-immunoprecipitation (Co-IP), proximity ligation assay (PLA), RNA immunoprecipitation (RIP)-qPCR, and mRNA stability assays were employed to investigate the interplay and potential mechanisms involving AURKB, heterogeneous nuclear ribonucleoprotein M (HNRNPM), and PSAT1.

RESULTS

AURKB was identified as an oncogene linked to advanced pathological staging and poor clinical outcomes in CRC. Its transcriptional upregulation was driven by H3K18 lactylation at its promoter. PSAT1 was further identified as a key downstream effector in AURKB-mediated CRC progression. Mechanistically, AURKB bound to HNRNPM and interfered with its interaction with PSAT1 mRNA, thereby suppressing HNRNPM-mediated mRNA degradation and ultimately increasing PSAT1 protein levels.

CONCLUSION

Our findings uncover a previously unappreciated, kinase-independent function of AURKB in CRC, redefining its therapeutic relevance beyond kinase inhibition. This highlights the need for broader targeting strategies, including PROTAC-mediated degradation of AURKB and pharmacological inhibition of the AURKB/PSAT1 axis, to fully harness its role in CRC treatment.

摘要

背景

极光激酶B（AURKB）是有丝分裂的关键调节因子，在包括结直肠癌（CRC）在内的多种恶性肿瘤中经常上调，且与预后不良相关。然而，AURKB抑制剂有限的临床疗效表明存在以前未被认识的致癌机制，值得进一步研究。

方法

通过生物信息学分析确定AURKB为研究重点，并通过单细胞RNA测序（scRNA-seq）和蛋白质免疫印迹法验证其在CRC中的高表达。染色质免疫沉淀（ChIP）-qPCR证实AURKB的转录激活归因于H3K18乳酸化。进行RNA测序（RNA-seq）和基因集富集分析（GSEA）以确定AURKB的下游靶点。使用体外和体内功能实验进一步研究AURKB/磷酸丝氨酸转氨酶1（PSAT1）轴在CRC中的作用。采用质谱、免疫共沉淀（Co-IP）、邻近连接分析（PLA）、RNA免疫沉淀（RIP）-qPCR和mRNA稳定性分析来研究AURKB、不均一核核糖核蛋白M（HNRNPM）和PSAT1之间的相互作用及潜在机制。

结果

AURKB被鉴定为与CRC晚期病理分期和不良临床结局相关的致癌基因。其转录上调由启动子处的H3K18乳酸化驱动。PSAT1被进一步确定为AURKB介导的CRC进展中的关键下游效应因子。机制上，AURKB与HNRNPM结合并干扰其与PSAT1 mRNA的相互作用，从而抑制HNRNPM介导的mRNA降解并最终增加PSAT1蛋白水平。