Abstract
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-1α (HIF-1α) for transcriptional regulation. HIF-1α 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-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α 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-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination–proteasomal degradation of HIF-1α protein in breast cancer.
Highlights
Hypoxia-inducible factor-1α (HIF-1α) is a versatile transcriptional factor that exerts its transactivation ability for transcriptional regulation [1]
HIF-1α is hydroxylated by prolyl-4-hydroxylases (PHDs) in the oxygen-dependent degradation domain (ODDD) at the proline residues (P402 and P564), which is recognized by its E3 ligase, von Hippel–Lindau protein (VHL), followed by ubiquitination, thereby leading to its proteasomal degradation
To investigate the association between TARBP2 and hypoxia, we utilized the cohort of breast cancer patients from the Cancer Genome Atlas (TCGA) and analyzed hypoxia scores, which were calculated using the mRNA-based signatures developed by Buffa and Winter [11,12]
Summary
Hypoxia-inducible factor-1α (HIF-1α) is a versatile transcriptional factor that exerts its transactivation ability for transcriptional regulation [1]. Deubiquitination of HIF-1α is an alternate pathway which inhibits degradation, and this process is facilitated by a group of deubiquitinating enzymes (DUBs). These deubiquitinases (DUBs) function via removing the ubiquitinated marks or editing the ubiquitin chains in the target proteins to recycle ubiquitin for maintaining ubiquitin homeostasis [4]. Several E3 ligases and DUBs have been individually reported to affect HIF-1α expression [4], the global regulation of these two processes is less well understood. TARBP2 is reported to promote tumor-induced angiogenesis through degradation of mRNAs coding for antiangiogenetic factors, including thrombospondin1/2 (THBS1/2), tissue inhibitor of metalloproteinases
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