Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis

作者全名："Nie, Dan; Tang, Xin; Deng, Haijun; Yang, Xiaojun; Tao, Junji; Xu, Fengli; Liu, Yi; Wu, Kang; Wang, Kai; Mei, Zhechuan; Huang, Ailong; Tang, Ni"

作者地址："[Nie, Dan; Tang, Xin; Deng, Haijun; Tao, Junji; Xu, Fengli; Liu, Yi; Wu, Kang; Wang, Kai; Huang, Ailong; Tang, Ni] Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Dept Infect Dis,Affiliated Hosp 2,Minist Educ, Chongqing 400010, Peoples R China; [Nie, Dan; Yang, Xiaojun] Chongqing Acad Tradit Chinese Med, Chongqing Hosp Tradit Chinese Med, Dept Gastroenterol, Chongqing 400016, Peoples R China; [Mei, Zhechuan] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400016, Peoples R China"

通信作者："Wang, K; Huang, AL; Tang, N (通讯作者)，Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Dept Infect Dis,Affiliated Hosp 2,Minist Educ, Chongqing 400010, Peoples R China.; Mei, ZC (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400016, Peoples R China."

来源：ADVANCED SCIENCE

ESI学科分类：PHYSICS

WOS号：WOS:001117530500001

JCR分区：Q1

影响因子：14.3

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：alternative splicing; HCC; nonmetabolic functions

摘要："Solute carrier family 27 member 5, a key enzyme in fatty acid transport and bile acid metabolism in the liver, is frequently expressed in low quantities in patients with hepatocellular carcinoma, resulting in poor prognosis. However, it is unclear whether SLC27A5 plays non-canonical functions and regulates HCC progression. Here, an unexpected non-canonical role of SLC27A5 is reported: regulating the alternative splicing of mRNA to inhibit the metastasis of HCC independently of its metabolic enzyme activity. Mechanistically, SLC27A5 interacts with IGF2BP3 to prevent its translocation into the nucleus, thereby inhibiting its binding to target mRNA and modulating PIP4K2A pre-mRNA splicing. Loss of SLC27A5 results in elevated levels of the PIP4K2A-S isoform, thus positively regulating phosphoinositide 3-kinase signaling via enhanced p85 stability in HCC. SLC27A5 restoration by AAV-Slc27a5 or IGF2BP3 RNA decoy oligonucleotides exerts an inhibitory effect on HCC metastasis with reduced expression of the PIP4K2A-S isoform. Therefore, PIP4K2A-S may be a novel target for treating HCC with SLC27A5 deficiency. A mechanism is proposed that SLC27A5 plays a noncanonical role in inhibiting HCC progression. SLC27A5 inhibits the conversion from PIP4K2A-L to PIP4K2A-S via interaction with IGF2BP3, and suppresses the PI3K/AKT pathway. These findings highlight PIP4K2A-S is a potential marker of diagnosis and prognosis for HCC. IGF2BP3 RNA decoy is a promising therapy for HCC patients with SLC27A5 deficiency.image"

基金机构："National Natural Science Foundation of China; The 111 Project [W0101]; Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [HZ2021006]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [JZD-M202000401, 2023YFC2306800]; Innovative and Entrepreneurial Team of Chongqing Talents Plan, Kuanren Talents and Dengfeng Program of the Second Affiliated Hospital of Chongqing Medical University; Science and Technology Research Program of Chongqing Municipal Education Commission; National Key Research and Development Program of China; [D20028]; [2023DBXM007]; [W0036]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (Grant No. 82272975, NT; U20A20392, AH; 82273238, KW), the 111 Project (No. D20028, AH), Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007, NT), Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0036, NT; W0101, KW), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Kuanren Talents and Dengfeng Program of the Second Affiliated Hospital of Chongqing Medical University, and the Science and Technology Research Program of Chongqing Municipal Education Commission grants HZ2021006 (NT) and JZD-M202000401 (NT), National Key Research and Development Program of China (2023YFC2306800, NT)."