FBXO30 functions as a tumor suppressor and an E3 ubiquitin ligase for hZIP1‑mediated HIF‑1α degradation in renal cell carcinoma

Abstract

Studies on clear cell renal cell carcinoma (ccRCC) are gaining momentum due to its high malignancy and potential to metastasize. F-box protein 30 (FBXO30) is a member of the F-box protein family; however, its role and mechanism in cancer remains to be fully elucidated. Western blotting, reverse transcription-quantitative PCR and immunohistochemsitry were performed to detect the expression levels of FBXO30 in ccRCC tissues and adjacent normal tissues. Tumor biological function assays and animal experiments were conducted to clarify the inhibitory effect of FBXO30 on the progression and metastasis of ccRCC. Protein half-life assay, MG132 inhibition assay, immunofluorescence assay and co-immunoprecipitation assay were performed to explore the ubiquitination mechanism of FBXO30 and HIF-1α. Zinc supplementation assay was used to verify the regulatory relationship between human ZRT, IRT-like protein 1 (hZIP1), FBXO30 and HIF-1α. The present study revealed that the expression levels of FBXO30 were lower in ccRCC tissues compared with those in normal adjacent tissues. In addition, FBXO30 inhibited the tumorigenesis and metastatic capacity of ccRCC cells in vivo and in vitro . FBXO30 mediated the ubiquitination and degradation of hypoxia-inducible factor-1α (HIF-1α) in ccRCC cells under normoxia, thereby inhibiting the oncogenic effect of HIF-1α. Notably, hZIP1 served as an upstream regulator of FBXO30, regulating the expression of FBXO30 and HIF-1α by recruiting Zn 2+ . In conclusion, the present data suggested that FBXO30 is a novel E3 ubiquitination ligase that can function as a tumor suppressor in ccRCC, and the hZIP1/Zn 2+ /FBXO30/HIF-1α axis may provide potential biomarkers or therapeutic targets for ccRCC.

Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation

“…This offers an alternative method to preserve de novo fatty acid synthesis during hypoxic conditions through the regulation of glutaminase 1 (GLS1), glutamate dehydrogenase 1 (GLUD1), and isocitrate dehydrogenase 1 (IDH1) by HIF-1α [ 55 , 56 ]. HIF-1α increases α-ketoglutarate production by upregulating GLS1 and E3 ubiquitin ligase SIAH2 [ 57 ], which subsequently controls the degradation of the α-ketoglutarate dehydrogenase complex (KGDH) [ 58 ].…”