组蛋白乳酸化增强的AURKB通过抑制hnrnpm介导的PSAT1 mRNA降解促进结直肠癌的进展。

IF 12.8 1区 医学 Q1 ONCOLOGY
Yuyi Li, Jinjin Peng, Di Wu, Qingxin Xie, Yichao Hou, Linjing Li, Xintian Zhang, Yu Liang, Jing Feng, Jiaqing Chen, Wangshuang Chen, Che Xu, Han Yao, Xiangjun Meng
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引用次数: 0

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)在内的各种恶性肿瘤中经常上调,并与不良预后相关。然而,AURKB抑制剂有限的临床疗效表明存在以前未被认识到的致癌机制,值得进一步研究。方法:通过生物信息学分析确定AURKB的优先级,并通过单细胞RNA测序(scRNA-seq)和western blot验证其在结直肠癌中的表达升高。染色质免疫沉淀(ChIP)-qPCR证实,AURKB的转录激活归因于H3K18的乙酰化。通过RNA测序(RNA-seq)和基因集富集分析(GSEA)确定AURKB的下游靶点。通过体外和体内功能实验进一步研究了AURKB/phosphoserine aminotransferase 1 (PSAT1)轴在CRC中的作用。采用质谱法、共免疫沉淀法(Co-IP)、近距离连接法(PLA)、RNA免疫沉淀法(RIP)-qPCR和mRNA稳定性分析研究了AURKB、异质核糖核蛋白M (HNRNPM)和PSAT1之间的相互作用和潜在机制。结果:AURKB被确定为与结直肠癌晚期病理分期和不良临床结果相关的癌基因。其转录上调是由启动子处的H3K18乳酸化驱动的。PSAT1被进一步鉴定为aurkb介导的CRC进展的关键下游效应因子。机制上,AURKB结合HNRNPM并干扰其与PSAT1 mRNA的相互作用,从而抑制HNRNPM介导的mRNA降解,最终增加PSAT1蛋白水平。结论:我们的研究结果揭示了AURKB在结直肠癌中以前未被发现的激酶独立功能,重新定义了它在激酶抑制之外的治疗相关性。这突出了需要更广泛的靶向策略,包括protac介导的AURKB降解和AURKB/PSAT1轴的药理抑制,以充分利用其在结直肠癌治疗中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Histone lactylation-boosted AURKB facilitates colorectal cancer progression by inhibiting HNRNPM-mediated PSAT1 mRNA degradation.

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.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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