复旦大学毛岸荣等研究人员合作发现，类器官模型鉴定USP3-AS1作为结直肠癌肝转移中的新型促进因子，其通过增加葡萄糖驱动的组蛋白乳酸化作用。2025年1月21日，《中国药理学报》在线发表了这项成果。

研究人员使用患者来源的类器官（PDO）模型探讨了长链非编码RNA（lncRNA）在结直肠癌肝转移（CRLM）过程中代谢重编程中的作用。研究人员建立了来自原发性肿瘤和配对肝转移病灶的五对PDO，并进行了微阵列分析。结果发现，USP3-AS1在CRLM来源的PDO中明显高表达，且其高表达水平与术后肝转移呈正相关，且与结直肠癌（CRC）患者的预后呈负相关。USP3-AS1过表达显著增强了PDO的球体形成效率和肝转移能力。基因集富集分析显示，USP3-AS1的上调显著富集了糖酵解和MYC信号通路。代谢组学分析证实，USP3-AS1促进了PDO中的糖酵解，而抑制糖酵解则部分缓解了USP3-AS1过表达对PDO生长和肝转移的影响。

研究人员揭示了USP3-AS1通过翻译后去泛素化稳定MYC，从而促进糖酵解。研究人员证明了USP3-AS1通过增加USP3 mRNA的稳定性，导致USP3蛋白的高表达，进而与MYC相互作用并通过去泛素化促进其稳定性。USP3-AS1–MYC–糖酵解调控轴通过促进H3K18乳酸化和CDC27表达来调控CRC的肝转移。总之，USP3-AS1通过诱导组蛋白乳酸化成为CRLM的一个新型促进因子。

据介绍，lncRNA在CRLM中常表现为失调。越来越多的证据将lncRNA与转移的多个阶段联系在一起，从初期的迁移到远端器官的定殖。

附：英文原文

Title: Organoid modeling identifies USP3-AS1 as a novel promoter in colorectal cancer liver metastasis through increasing glucose-driven histone lactylation

Author: Zhou, Jia-min, Dai, Wei-xing, Wang, Ren-jie, Xu, Wei-qi, Xiang, Zhen, Wang, Yi-xiu, Zhang, Ti, Zhao, Yi-ming, Wang, Lu, Mao, An-rong

Issue&Volume: 2025-01-21

Abstract: Dysregulation of long non-coding RNAs (lncRNAs) is common in colorectal cancer liver metastasis (CRLM). Emerging evidence links lncRNAs to multiple stages of metastasis from initial migration to colonization of distant organs. In this study we investigated the role of lncRNAs in metabolic reprogramming during CRLM using patient-derived organoid (PDO) models. We established five pairs of PDOs from primary tumors and matched liver metastatic lesions, followed by microarray analysis. We found that USP3-AS1 was significantly upregulated in CRLM-derived PDOs compared to primary tumors. High level of USP3-AS1 was positively associated with postoperative liver metastasis and negatively correlated with the prognosis of colorectal cancer (CRC) patients. Overexpression of USP3-AS1 significantly enhanced both sphere formation efficiency and liver metastasis in PDOs. Gene set enrichment analysis revealed that USP3-AS1 upregulation significantly enriched glycolysis and MYC signaling pathways. Metabolomics analysis confirmed that USP3-AS1 promoted glycolysis in PDOs, whereas glycolysis inhibition partially attenuated the effects of USP3-AS1 overexpression on PDO growth and liver metastasis. We revealed that USP3-AS1 stabilized MYC via post-translational deubiquitination, thereby promoting glycolysis. We demonstrated that USP3-AS1 increased the stability of USP3 mRNA, resulting in higher USP3 protein expression. The elevated USP3 protein then interacted with MYC and promoted its stability by deubiquitination. The USP3-AS1–MYC–glycolysis regulatory axis modulated liver metastasis by promoting H3K18 lactylation and CDC27 expression in CRC. In conclusion, USP3-AS1 is a novel promoter of CRLM by inducing histone lactylation.

DOI: 10.1038/s41401-024-01465-8

Source: https://www.nature.com/articles/s41401-024-01465-8