Intron Retention of DDX39A Driven by SNRPD2 is a Crucial Splicing Axis for Oncogenic MYC/Spliceosome Program in Hepatocellular Carcinoma
Cunjie Chang, Lina Li, Ling Su, Fan Yang, Quanxiu Zha, Mengqing Sun, Tao Lin, Menglan Wang, Kangli Song, Liangyu Jiang, Haojin Gao, Yexin Liang, Chao Xu, C.-C. Yong, Minmin Wang, Jiacheng Huang, Jing Liu, Weiwei Jin, Wenyuan Lv, Heng Dong, Qian Li, Fangtian Bu, Shuanghong Yan, Haoxiang Qi, Shujuan Zhao, Yingshuang Zhu, Yu Wang, Junping Shi, Yiting Qiao, Jian Xu, Benoı̂t Chabot, Jianxiang Chen
Abstract
RNA splicing is a dynamic molecular process in response to environmental stimuli and is strictly regulated by the spliceosome. Sm proteins, constituents of the spliceosome, are key components that mediate splicing reactions; however, their potential role in hepatocellular carcinoma (HCC) is poorly understood. In the study, SNRPD2 (PD2) is found to be the most highly upregulated Sm protein in HCC and to act as an oncogene. PD2 modulates DDX39A intron retention together with HNRNPL to sustain the DDX39A short variant (39A_S) expression. Mechanistically, 39A_S can mediate MYC mRNA nuclear export to maintain high MYC protein expression, while MYC in turn potentiates PD2 transcription. Importantly, digitoxin can directly interact with PD2 and has a notable cancer-suppressive effect on HCC. The study reveals a novel mechanism by which DDX39A senses oncogenic MYC signaling and undergoes splicing via PD2 to form a positive feedback loop in HCC, which can be targeted by digitoxin.