pVHL‐mediated degradation of HIF‐2α regulates estrogen receptor α expression in normoxic breast cancer cells

Abstract

Estrogen receptor a (ERa) functions as a transcription factor for genes involved in estrogen-dependent development of breast cancer cells. We demonstrate here that knockdown of hypoxia-inducible factor (HIF)-2a, but not of HIF-1a, increases endogenous ERa protein expression in normoxia and hypoxia. The von Hippel-Lindau protein (pVHL)-dependent degradation of HIF-2a participates in the regulation of ERa expression. Additionally, HIF2a forms a protein complex with ERa, and amino acids 396-823 of HIF-2a physically interact with the ligand-binding domain of ERa. These results indicate that HIF-2a functions as a negative regulator of ERa expression in breast cancer, especially in normoxia.

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

“…While p-VHL plays an important role in the recognition and subsequent degradation of HIF-2α, nuclear translocation is another crucial means of executing its transcriptional activity (42,43). Our data first provided the evidence that the COX-2/PGE2 axis regulates HIF-2α levels through a p-VHL-mediated degradation pathway during posttranscriptional processing but not at the transcription level.…”

SHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel‐Lindau protein ubiquitination and degradation

“…The pVHL‐mediated ubiquitination and subsequent proteasomal degradation is regarded as an important way for HIF‐2α to maintain stability. Considering that Caki‐1 and ACHN cells express pVHL but 769‐P cells do not, 34 and that pVHL participates in the degradation of HIF‐2α, 35 we focused on whether SHARPIN works through pVHL. We tested the level of pVHL in Caki‐1 and ACHN cells when SHARPIN was downregulated, and found it increased (Figure 2H ).…”

VHL Ser65 mutations enhance HIF2α signaling and promote epithelial-mesenchymal transition of renal cancer cells

“…Germline heterozygous mutation of the VHL tumor suppressor gene, located on 3p25.3, encoding VHL tumor suppressor protein (pVHL), has been identified as the leading cause of VHL disease. Mutations leading to VHL loss cause a number of diseases with divergent features, including VHL disease, sporadic tumors (all tumors associated with VHL disease), familial erythrocytosis type 2, and breast cancer [ 7 , 8 ]. pVHL is best known as the substrate-binding subunit of an E3 ubiquitin ligase, which binds the transcription elongation factors C and B (elongin C/B) forms the VCB complex, then interacts with Cullin-2 (CUL2) and the RING finger protein RBX1 forming the VCB-CR complex(3).…”