CAND1 drives lipid metabolism and hepatocellular carcinoma progression by regulating FBXO11-mediated hnRNPA2B1 ubiquitination

Abstract

Abstract Background Aberrant lipid metabolism marks one of characteristic features of hepatocellular carcinoma (HCC). Here, we define the function and mechanism of CAND1 in lipid metabolism and progression of HCC in vitro and in vivo, and postulate CAND1/FBXO11/hnRNPA2B1 as a suitable therapeutic target for HCC. Methods We performed IHC staining, western blot analysis and prognostic analyses of CAND1 in HCC to define its prognostic value. The functions of CAND1 were evaluated through in vitro and in vivo experiments. RNA-Seq and lipidomic assays followed by serial biochemical experiments including mass spectrometry, immunoprecipitation, GST pulldown, and ubiquitination were performed to dissect the underlying mechanism. Results CAND1 was highly expressed in HCC tissues and cell lines and served as an independent prognostic risk factor for HCC. CAND1 promoted HCC cell proliferation, colony formation, migration, and invasion in vitro. CAND1 facilitated tumor growth and metastasis in vivo. Mechanism studies demonstrated that CAND1 promoted lipid synthesis through disrupting Skp1-Cul1-FBXO11 complex assembly. Furthermore, we identified hnRNPA2B1 as a novel FBXO11-binding partner mediating CAND1 function. FBXO11 directly bound to hnRNPA2B1 and promoted hnRNPA2B1 lysine 27 (K27)- and K48-linked ubiquitination and subsequent degradation. Interfering CAND1 by shRNA significantly reduced tumor burden in primary mouse liver cancer model and PDX model. Conclusions CAND1 promoted HCC and regulated lipid synthesis by upregulating hnRNPA2B1 through dissociating Skp1-Cul-FBXO11 complex, which caused hnRNPA2B1 ubiquitination and degradation. Targeting CAND1-SCFFBXO11-hnRNPA2B1 axis may be a novel strategy against HCC.