| 4 | FBXW7βloss-of-function enhances FASN-mediated lipogenesis and promotes colorectal cancer growth显示文摘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. | 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 | 2023 | Signal Transduction and Targeted Therapy2023，8，6： | 0 |
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