TARBP2 Suppresses Ubiquitin-Proteasomal Degradation of HIF-1α in Breast Cancer

TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1 alpha (HIF-1 alpha) for transcriptional regulation. HIF-1 alpha is prone to be rapidly destabilized by the ubiquitination-proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1 alpha protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1 alpha protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1 alpha (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1 alpha were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1 alpha and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination-proteasomal degradation of HIF-1 alpha protein in breast cancer.

Automated summary

This study reveals the regulatory role of TARBP2 in the ubiquitination-proteasomal degradation of HIF-1 alpha protein in breast cancer, showing its significance in cancer progression.