增强的从头脂肪生成对于肝细胞癌 (HCC) 至关重要。 cullin 相关和 neddylation 解离 1 (CAND1) 异常高表达与 HCC 临床预后不良相关。 SKP1-Cullin-1-F-box (SCF) 复合物由 SKP1、Cullin-1 和 F-box 蛋白 (FBP) 组成，执行包括脂肪生成在内的多种功能。 SCF复合物受CAND1调节，但CAND1是否以及如何通过调节SCF复合物和脂肪生成促进HCC尚不清楚。我们利用HCC样本分析CAND1表达与生存和预后等临床病理特征的相关性。通过细胞增殖、集落形成和迁移测定来测量 CAND1、FBXO11 和异质核核糖核蛋白 A2/B1 (hnRNPA2B1) 的体外功能。在多种小鼠肝癌模型中测试了体内功能，包括患者来源的异种移植物 (PDX)、细胞系来源的异种移植物和 AKT/NRASV12 诱导的原发性肝癌模型。注射靶向CAND1的腺相关病毒（AAV-shCAND1）以评估靶向CAND1的治疗效果。进行RNA-Seq和脂质组学测定，然后进行一系列生化实验，包括质谱、免疫沉淀和GST Pull-down，以剖析潜在的机制。CAND1通过破坏SCF复合物组装和脂质积累来促进脂质合成基因的表达。此外，我们确定 hnRNPA2B1 是一种新型 F-box 蛋白 11 (FBXO11) 结合伴侣。 FBXO11 直接与 hnRNPA2B1 结合，促进 hnRNPA2B1 泛素化和随后的降解。我们对 AAV-shCAND1 注射治疗效果的评估证实，靶向 CAND1-SCFFBXO11 -hnRNPA2B1A 信号轴具有治疗效果。 CAND1 下调显着降低了原发性小鼠肝癌模型和 PDX 模型中的肿瘤负荷。我们的结果强调，CAND1 与 HCC 不良预后相关，并通过解离 SCF 复合物来调节脂质代谢重编程。靶向 CAND1-SCFFBXO11 -hnRNPA2B1 轴可能是 HCC 治疗的一种新策略。© 2023 作者。约翰·威利出版的《临床与转化医学》

Enhanced de novo lipogenesis is essential for hepatocellular carcinoma (HCC). Abnormally high cullin-associated and neddylation-dissociated 1 (CAND1) expression is associated with poor clinical prognosis in HCC. The SKP1-Cullin-1-F-box (SCF) complex consists of the SKP1, Cullin-1 and F-box proteins (FBPs) and performs multiple functions including adipogenesis. SCF complex was modulated by CAND1, but Whether and how the CAND1 promotes HCC by regulating SCF complex and lipogenesis are unknown.HCC samples were used to analyze the correlations between CAND1 expression and clinicopathological characteristics such as survival and prognosis. The in vitro functions of CAND1, FBXO11 and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) were measured by cell proliferation, colony formation and migration assays. The in vivo functions were tested in multiple mouse liver cancer models including patient-derived xenograft (PDX), cell line-derived xenograft and AKT/NRASV12-induced primary liver cancer models. Injections of adeno-associated virus targeting CAND1 (AAV-shCAND1) were performed to evaluate the therapeutic efficacy of targeting CAND1. RNA-Seq and lipidomic assays followed by serial biochemical experiments including mass spectrometry, immunoprecipitation and GST pull-down were performed to dissect the underlying mechanisms.CAND1 promoted the expression of lipid synthesis genes by disrupting SCF complex assembly and lipid accumulation. Furthermore, we identified hnRNPA2B1 as a novel F-box protein 11 (FBXO11)-binding partner. FBXO11 directly bound to hnRNPA2B1 and promoted hnRNPA2B1 ubiquitination and subsequent degradation. Our evaluations of the therapeutic efficacy of AAV-shCAND1 injections confirmed that targeting the CAND1-SCFFBXO11 -hnRNPA2B1A signalling axis was therapeutically effective. CAND1 downregulation significantly reduced the tumour burden in a primary mouse liver cancer model and a PDX model.Our results highlight that CAND1 is associated with poor prognosis in HCC and regulates lipid metabolic reprogramming by dissociating the SCF complex. Targeting the CAND1-SCFFBXO11 -hnRNPA2B1 axis may be a novel strategy for HCC treatment.© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.