FBXW7βloss-of-function enhances FASN-mediated lipogenesis and promotes colorectal cancer growth  

作　　者：Wenxia Wei Baifu Qin Weijie Wen Boyu Zhang Haidan Luo Yuzhi Wang Hui Xu Xiaoshan Xie Sicheng Liu Xin Jiang Mengan Wang Qin Tang Jiayu Zhang Runxiang Yang Zongmin Fan Haiwen Lyu Junzhong Lin Kai Li Mong-Hong Lee 

机构地区：[1]Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,510655,China [2]Guangdong Institute of Gastroenterology,Guangzhou,510655,China [3]Second Department of Medical Oncology,The Third Affiliated Hospital of Kunming Medical University,Kunming,650118,China [4]Guangzhou Institute of Pediatrics,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou,510623,China [5]Department of Colorectal Surgery,Cancer Center,Sun Yat-sen University,Guangzhou,510060,China [6]Department of Oncology,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,510655,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第6期3123-3143,共21页信号转导与靶向治疗（英文）

基　　金：supported by National Key R&D Program of China(2020YFA0803300),the Basic and Applied Basic Research Program of Guangzhou City(202102020084);the Basic and Applied Basic Research Program of Guangdong Province(2023A1515030245),the Natural Science Foundation of Guangdong Province(2021A1515012081);the National Natural Science Foundation of China(81630072);the Guangzhou Science and Technology Program Project(202206010167).

摘　　要：Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor.FBXW7 is a highly mutated gene in CRC,but its biological functions in cancer are not fully characterized.Here,we report that FBXW7β,a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC,is an E3 ligase of fatty acid synthase(FASN).Cancer-specific FBXW7βmutations that could not degrade FASN can lead to sustained lipogenesis in CRC.COP9 signalosome subunit 6(CSN6),an oncogenic marker of CRC,increases lipogenesis via interacting with and stabilizing FASN.Mechanistic studies show that CSN6 associates with both FBXW7βand FASN,and antagonizes FBXW7β’s activity by enhancing FBXW7βautoubiquitination and degradation,which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation,thereby regulating lipogenesis positively.Both CSN6 and FASN are positively correlated in CRC,and CSN6-FASN axis,regulated by EGF,is responsible for poor prognosis of CRC.The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab.Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC.Thus,CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.

关 键 词：FBXW7 SUSTAINED FASN 

分 类 号：R735.34[医药卫生—肿瘤]