Cullin‐associated and neddylation‐dissociated 1 regulate reprogramming of lipid metabolism through SKP1‐Cullin‐1‐F‐box^FBXO11‐mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma

Abstract

BackgroundEnhanced 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.MethodsHCC 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.ResultsCAND1 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.ConclusionsOur 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.

The Regulatory Network of hnRNPs Underlying Regulating PKM Alternative Splicing in Tumor Progression

“…In addition to glucose metabolism, the post-translation modifications of hnRNPs exert other aspects on cellular metabolism. The ubiquitination of PTBP1 and hnRNPA2/B1 affect lipogenesis in intrahepatic cholangiocarcinoma [87] and hepatocellular carcinoma [88]. Additionally, hnRNPK phosphorylation influences mRNA metabolism [89].…”

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma

“…Consequently, CAND1 has been identified as an oncogene of HCC. [ 85 ] The NAD(P)H quinone oxidoreductase-1/p53 target SREBP1 forms a signaling axis to enhance the content of lipids, including TAG and cholesterol, and maintain Snail protein levels by restraining its ubiquitylation, thus mediating the EMT, angiogenesis, and proliferation while inhibiting autophagy in HCC, which makes it a potential prognostic biomarker. [ 86 ] Liu et al [ 87 ] reported that stomatin-like protein 2 (SLP2) could be a prospective prognostic biomarker for HCC.…”

“…Zuo et al [ 104 ] developed a new-type nanoplatform based on polymeric nanoparticles and poly (lactic/glycolic) acid, encapsulating si-LINC00958 and spermidine, which can remarkably suppress the growth and prolong the overall survival of HCC model mice without prominent hepatotoxicity and nephrotoxicity. Zhang et al [ 85 ] utilized the adeno-associated virus injections to knockdown CAND1, downregulating the expression of downstream genes, including FASN, ACC1, and ACLY. This had a restraining effect on HCC growth by reducing the accumulation of lipids, which demonstrates that regulation of the CAND1-SCFFBXO11-hnRNPA2B1 axis may be a potential therapeutic target.…”

A novel model based on ubiquitination-related gene to predict prognosis and immunotherapy response in hepatocellular carcinoma

“…Nowadays, many scholars have applied URGs related characteristics to forecast the future course and immune reaction of various types of cancer, such as lung adenocarcinoma and endometrial cancer, the prognostic signature based on URGs performed well in predicting the infiltration of immune cells and the level of tumor mutation burden (TMB) within the TME and the effectiveness of immunotherapy for cancer treatment [ 13 , 14 ]. There were several studies have uncovered the relationship of URGs and the initiation and development of HCC, nevertheless, the role of URGs in HCC has not been systematically analyzed [ 15 , 16 ].…”