CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA‐binding motif protein 38
Yi He,
Shenqi Han,
Han Li,
Yu Wu,
Wenlong Jia,
Zeyu Chen,
Yonglong Pan,
Ning Cai,
Jingyuan Wen,
Ganxun Li,
Junnan Liang,
Jianping Zhao,
Qiumeng Liu,
Huifang Liang,
Zeyang Ding,
Zhao Huang,
Bixiang Zhang
Affiliations
Yi He
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Shenqi Han
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Han Li
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Yu Wu
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Wenlong Jia
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Zeyu Chen
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Yonglong Pan
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Ning Cai
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Jingyuan Wen
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Ganxun Li
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Junnan Liang
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Jianping Zhao
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Qiumeng Liu
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Huifang Liang
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Zeyang Ding
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Zhao Huang
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Bixiang Zhang
Hepatic Surgery Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Abstract cAMP responsive element binding protein 3 (CREB3), belonging to bZIP family, was reported to play multiple roles in various cancers, but its role in hepatocellular carcinoma (HCC) is still unclear. cAMP responsive element binding protein 3 like 3 (CREB3L3), another member of bZIP family, was thought to be transcription factor (TF) to regulate hepatic metabolism. Nevertheless, except for being TFs, other function of bZIP family were poorly understood. In this study, we found CREB3 inhibited growth and metastasis of HCC in vitro and in vivo. RNA sequencing indicated CREB3 regulated AKT signaling to influence HCC progression. Mass spectrometry analysis revealed CREB3 interacted with insulin receptor (INSR). Mechanistically, CREB3 suppressed AKT phosphorylation by inhibiting the interaction of INSR with insulin receptor substrate 1 (IRS1). In our study, CREB3 was firstly proved to affect activation of substrates by interacting with tyrosine kinase receptor. Besides, CREB3 could act as a TF to transactivate RNA‐binding motif protein 38 (RBM38) expression, leading to suppressed AKT phosphorylation. Rescue experiments further confirmed the independence between the two functional manners. In conclusion, CREB3 acted as a tumor suppressor in HCC, which inhibited AKT phosphorylation through independently interfering interaction of INSR with IRS1, and transcriptionally activating RBM38.
