The long non-coding RNA-encoded microprotein MKKS3 drives colorectal cancer chemoresistance.

Hui-Fang Hu, Qi Zhou, Jia-Zhen Huang, Jia-Ying Fu, Zhi-Ting Zuo, Qing-Yu He

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Article in Experimental & molecular medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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Hui-Fang Hu *MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. hhf2023@jnu.edu.cn.

Qi Zhou *MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.

Jia-Zhen HuangMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.

Jia-Ying FuMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.

Zhi-Ting ZuoMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.

Qing-Yu HeMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. tqyhe@jnu.edu.cn.

Funding

National Natural Science Foundation of China (National Science Foundation of China) 82202842，82573360Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation) 2021A1515111126，2023A1515010324，2026A1515012819

6 · The paper itself

Abstract

Although oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed owing to oxaliplatin resistance. The roles of long non-coding RNAs-encoded microproteins in oxaliplatin chemoresistance remain inadequately explored. In this study, a CRISPR/Cas9 library was developed to target previously identified 314 microproteins translated from long non-coding RNAs, followed by functional screening. This strategy identified MKKS3, encoded by NR_072977, as a key regulator of chemoresistance in CRC. A pan-cancer analysis integrating translatomics and proteomics revealed widespread MKKS3 expression across various human cancers. Our experiments demonstrated that MKKS3 promotes chemoresistance in CRC and drives iCAF-to-myCAF conversion. Mechanistically, MKKS3 interacts with TRIM29 to facilitate DNA repair complex assembly and induce STING ubiquitination, thus suppressing IFNβ secretion and further activating fibroblasts. These activated fibroblasts secrete increased amounts of TGFβ, which in turn downregulates STING expression. Additionally, DENR functions as a suppressor of MKKS3 expression and regulates its translation. The natural compound 1-Hydroxybaccatin I inhibits the MKKS3-TRIM29 interaction, and its combination treatment with oxaliplatin enhances therapeutic outcomes of CRC by promoting CD8

Indexed as

Colorectal NeoplasmsDrug Resistance, NeoplasmRNA, Long NoncodingAnimalsAntineoplastic AgentsCell Line, TumorDNA-Binding ProteinsGene Expression Regulation, NeoplasticHumansMiceMicropeptidesOxaliplatinTranscription FactorsAntineoplastic AgentsDNA-Binding ProteinsMicropeptidesOxaliplatinRNA, Long NoncodingTranscription Factors

Identifiers

PMID42686984

DOI10.1016/j.molp.2023.10.016

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