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

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.