β‐TrCP upregulates HIF‐1 in prostate cancer cells

• Published in: The Prostate 2019-03, Vol.79 (4), p.403-413
• Main Authors: Cohen, Maya, Amir, Sharon, Golan, Maya, Ben‐Neriah, Yinon, Mabjeesh, Nicola J.
• Format: Article
• Language: English
• Subjects: Hsp70 protein; Hypoxia; Ischemia; Prostate cancer; Proteasomes; Protein expression; Proteins; Proteolysis; Proteomics; Transcription; Transducin; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.23746

The substantial availability of hypoxia‐inducible factor 1 (HIF‐1) for pathophysiological states, such as malignancies and ischemia, is primarily regulated post‐translationally through the ubiquitin proteolytic system. The balance between degradation and stabilization of HIF‐1α protein is determined by specific E3 ligases. In our search for new E3 ligases that might affect HIF‐1α protein expression, we studied the effects of beta‐transducin repeat‐containing protein (β‐TrCP) on the hypoxic pathway in cancer cells. β‐TrCP is overexpressed in many tumors and regulates various cellular processes through mediating the degradation of important targets. Unexpectedly, we found that β‐TrCP overexpression increases HIF‐1α protein expression level as well as HIF‐1 transcriptional activity by stabilizing HIF‐1α protein and preventing its ubiquitination and proteasomal degradation in prostate cancer cells. By using a proteomic approach, we succeeded in demonstrating that β‐TrCP interferes with the association between HIF‐1α and HSP70/CHIP, a HIF‐1α established E3 ligase complex. Whereas the E3 ligase activity of β‐TrCP is well known, antagonizing another E3 ligase is a new mechanism of action of this important E3. We suggest that destroying or suppressing β‐TrCP and thereby interrupting the HIF‐1 pathway, could be valuable antitumor therapy.