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journal article·2024-09Open access

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, Lin Tao, Menglan Wang, Kangli Song, Liangyu Jiang, Haojin Gao, Yexin Liang, Chao Xu, Caiyu 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, Benoit Chabot, Jianxiang Chen

Advanced Science· Volume 11· Issue 35
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: RNA Research and Splicing · RNA modifications and cancer · RNA and protein synthesis mechanisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Pharmacy and Department of Hepatology the Affiliated Hospital of Hangzhou Normal University Hangzhou Normal University Hangzhou 311121 P. R. China

Medical Molecular Biology Laboratory Medical College Jinhua University of Vocational Technology Jinhua 321016 P.R. China

School of Public Health Hangzhou Normal University Hangzhou 311121 P. R. China

Laboratory of Cancer Genomics Division of Cellular and Molecular Research National Cancer Centre Singapore 169610 Singapore

The First Affiliated Hospital Key Laboratory of Combined Multi‐Organ Transplantation Ministry of Public Health Key Laboratory of Organ Transplantation of Zhejiang Province School of Medicine Zhejiang University Hangzhou 310003 P. R. China

Hepatobiliary and Liver transplantation Department of Hainan Digestive Disease Center The Second Affiliated Hospital of Hainan Medical University Haikou 570216 P. R. China

Département de Microbiologie et d'Infectiologie Faculté de Médecine et des Sciences de la Santé Université de Sherbrooke Sherbrooke QC J1E 4K8 Canada

Key Laboratory of Elemene Class Anti‐Cancer Chinese Medicines Engineering Laboratory of Development and Application of Traditional Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province School of Pharmacy Hangzhou Normal University Hangzhou 311121 P. R. China

Funding

Innovative Research Group Project of the National Natural Science Foundation of China · National Natural Science Foundation of China · National Outstanding Youth Science Fund Project of National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities · Natural Science Foundation of Zhejiang Province · Zhejiang Traditional Chinese Medicine Administration

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