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 FBXW7β mutations 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 FBXW7β and FASN, and antagonizes FBXW7β’s activity by enhancing FBXW7β autoubiquitination 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.

肿瘤的生物合成需求需要连续的脂肪酸从头合成。FBXW7是结直肠癌中高度突变的基因，但其在癌症中的生物学功能尚未完全表征。在此，我们报道FBXW7β是一种位于细胞质中且在CRC中频繁突变的FBXW7亚型，是脂肪酸合酶(FASN)的E3连接酶。无法降解 FASN 的癌症特异性 FBXW7β 突变可导致 CRC 中的持续脂肪生成。COP9 信号体亚基 6 (CSN6) 是 CRC 的致癌标志物，通过与 FASN 相互作用并稳定 FASN 来增加脂肪生成。机理研究表明，CSN6 与 FBXW7β 和 FASN 结合，并通过增强 FBXW7β 自身泛素化和降解来拮抗 FBXW7β 的活性，从而阻止 FBXW7β 介导的 FASN 泛素化和降解，从而积极调节脂肪生成。CSN6和FASN均与CRC呈正相关，且受EGF调控的CSN6-FASN轴是CRC预后不良的原因。EGF-CSN6-FASN轴促进肿瘤生长，暗示奥利司他和西妥昔单抗组合的治疗策略。患者来源的异种移植实验证明了奥利司他和西妥昔单抗组合在抑制 CSN6/FASN 高 CRC 肿瘤生长方面的有效性。因此，CSN6-FASN 轴重新编程脂肪生成以促进肿瘤生长，是结直肠癌癌症干预策略的目标。