2. Academic Validation
  3. CRTC2 Forms Co-Condensates with YTHDF2 That Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance

CRTC2 Forms Co-Condensates with YTHDF2 That Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance

  • Cancer Res. 2025 Jun 2;85(11):2046-2066. doi: 10.1158/0008-5472.CAN-24-3196.
Meixi Wang # 1,  Fangdi Zou # 1,  Shengxin Wang # 1,  Yichen Yang 2,  Cong Xia 1,  Lu Chen 3,  Ben Liu 4,  Lian Li 4,  Mulin Jun Li 5,  Haixin Li 6,  Weijie Song 7,  Ruifang Niu 1,  Zhiyong Yuan 8,  Jie Yang 9,  Xiangchun Li 2,  Kexin Chen 4,  Zhiqiang Wu 8,  Zeyun Mi 1
Affiliations

Affiliations

  • 1 Department of Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 2 Tianjin Cancer Institute, Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 3 Department of Hepatobiliary Cancer, Liver Cancer Research Center, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 4 Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 5 Department of Bioinformatics, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
  • 6 Cancer Biobank, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 7 Laboratory Animal Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 8 Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 9 State Key Laboratory of Experimental Hematology, Key Laboratory of Cellular and Molecular Immunology in Tianjin, and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
  • # Contributed equally.
PMID: 40036155 DOI: 10.1158/0008-5472.CAN-24-3196
Abstract

As the third most common cause of cancer-related mortality, hepatocellular carcinoma (HCC) is a global health concern. Despite its prevalence, treatment options are limited, underscoring the need to identify potential therapeutic targets and strategies. In this study, we identified amplification of cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2), situated in the 1q21.3 region, due to copy-number alterations in HCC. In a cohort of patients with HCC, CRTC2 protein levels were frequently elevated and correlated with poor prognosis. Genetic deletion of Crtc2 significantly impeded the onset and progression of HCC in mouse models. CRTC2 formed cytoplasmic condensates that recruited the N6-methyladenosine (m6A) reader YTHDF2. Furthermore, CRTC2 promoted the translocation of m6A-modified mRNAs from decay sites to polyribosomes by interacting with PABP1. The activities of CRTC2 counteracted YTHDF2-mediated mRNA degradation to enhance the translational efficiency of specific mRNAs, including those encoding LRP5 and c-Jun. Targeting Crtc2 in hepatocytes using AAV8.sgCrtc2 elicited substantial therapeutic benefits in HCC mouse models and significantly enhanced the sensitivity to lenvatinib. Together, this research elucidates the pivotal role and underlying molecular mechanisms of CRTC2 in hepatocarcinogenesis and lenvatinib resistance, highlighting its potential clinical and therapeutic applications. Significance: CRTC2 hijacks the YTHDF2-m6A pathway to increase translation of c-Jun and promote hepatocellular carcinoma development and lenvatinib resistance, indicating that CRTC2 is a promising biomarker and therapeutic target.

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