Eloc, also known as TCEB1, encodes elongin C, a key component of the VCB-CR (pVHL, elongin C, elongin B, cullin 2 and ring box 1) E3 ubiquitin ligase complex. This complex plays a crucial role in oxygen sensing and the degradation of hypoxia-inducible factors, thus being important in multiple biological processes related to oxygen regulation [1].

In a proband with von Hippel-Lindau disease (VHL) but without a detectable VHL mutation, a de novo pathogenic variant in ELOC (NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys)) was identified. The p.Tyr79Cys substitution, a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC), mimics the effects of pVHL deficiency on hypoxic signalling. Analysis of the proband's RCC showed similar findings to somatically ELOC-mutated RCC, suggesting pathogenic ELOC variants as a novel cause for VHL disease [1].

Biallelic ELOC-inactivated RCC, with ELOC mutations in combination with ELOC deletions on chromosome 8q, is considered a novel subtype of renal cancer. Biallelic ELOC and biallelic VHL aberrations were mutually exclusive, and no TSC1, TSC2, or mTOR mutations were identified in ELOC-mutated RCC with biallelic ELOC inactivation, supporting the notion of a distinct tumor entity [2]. ELOC-mutated RCC is also recognized as a novel molecularly defined epithelial renal tumour in the 2022 WHO classification of urogenital tumours [3,5,6,7,8].

In colorectal cancer, USP51 directly binds to Elongin C and forms a functional complex with VHL E3 ligase to regulate the ubiquitin-dependent proteasomal degradation of HIF1A. SUMOylation of ELOC at K32 inhibits its binding to USP51, while SENP1-mediated deSUMOylation promotes this binding, facilitating HIF1A deubiquitination and stabilization, and promoting cancer stemness and chemoresistance [4].

In conclusion, Eloc is essential for the proper function of the VCB-CR E3 ubiquitin ligase complex in oxygen sensing and hypoxia-inducible factor degradation. Its mutations are associated with the development of von Hippel-Lindau disease and a novel subtype of renal cell carcinoma. Studies on Eloc-related mutations in these disease models help to understand the molecular mechanisms of these diseases, providing potential insights for diagnosis and treatment.