The cancer-testis lncRNA lnc-CTHCC promotes hepatocellular carcinogenesis by binding hnRNP K and activating YAP1 transcription
Anliang Xia, Wenwen Yuan, Qiang Wang, Jianbo Xu, Yayun Gu, Liansheng Zhang, Chen Chen, Zhangding Wang, Di Wu, Qifeng He, Weiwei Yu, Fei Wang, Cailin Xue, Yan Zhang, Guojian Bao, Xuewen Tao, Siyuan Liu, Shouyu Wang, Zhibin Hu, Beicheng Sun
Abstract
Cancer-testis (CT) genes participate in the initiation and progression of cancer, but the role of CT-associated long non-coding RNAs (CT-lncRNAs) in hepatocellular carcinoma (HCC) is still elusive. Here, we discovered a conserved CT-lncRNA, named lnc-CTHCC, which was highly expressed in the testes and HCC. A lnc-CTHCC-knockout (KO) mouse model further confirmed that the global loss of lnc-CTHCC inhibited the occurrence and development of HCC. In vitro and in vivo assays also showed that lnc-CTHCC promoted HCC growth and metastasis. Mechanistically, lnc-CTHCC bound to heterogeneous nuclear ribonucleoprotein K (hnRNP K), which was recruited to the YAP1 promoter for its activation. Additionally, the N6-methyladenosine (m6A) modification was mediated by N6-adenosine-methyltransferase 70-kDa subunit (METTL3) and recognized by insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)/IGF2BP3, which maintained lnc-CTHCC stability and increased its expression in HCC. Together, our results show that lnc-CTHCC directly binds to hnRNP K and promotes hepatocellular carcinogenesis and progression by activating YAP1 transcription, suggesting that lnc-CTHCC is a potential biomarker and therapeutic target of HCC. Sun and colleagues identify lnc-CTHCC, a cancer-testis lncRNA that binds to hnRNP K, activates YAP1 transcription and promotes hepatocellular carcinogenesis.