HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation

Lavinia Nardinocchi,Rosa Puca,Gabriella D'Orazi

doi:10.18632/aging.100254

Abstract

Many human diseases are characterized by the development of tissue hypoxia. Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration, such as angiogenesis, survival, and alterations in metabolism. The levels of HIF-1α subunit are increased in most solid tumors not only by low oxygen but also by growth factors and oncogenes and correlate with patient prognosis and treatment failure. The link between HIF-1α and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that HIF-1α protects against drug-induced apoptosis by antagonizing the function of the tumor suppressor p53. HIF-1α upregulation induced proteasomal degradation of homeodomain-interacting protein kinase-2 (HIPK2), the p53 apoptotic activator. Inhibition of HIF-1α by siRNA, HIF-1α-dominant negative or by zinc re-established the HIPK2 levels and the p53-mediated chemosensitivity in tumor cells. Our findings identify a novel circuitry between HIF-1α and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies.

Highlights

HIPK2 is a potential tumor suppressor gene; it is a nuclear serine/threonine kinase that acts as corepressors for transcription factors [1] and is considered a central switch in the targeting of cells toward apoptosis upon genotoxic stress by phosphorylating tumor suppressor p53 at serine 46 (Ser46) [2,3]
We have shown that HIPK2 represses the Hypoxia‐inducible factor (HIF)-1α transcription, HIPK2 knock-down leads to HIF-1α upregulation with induction of a “constitutive hypoxic” phenotype [13]
We first analyzed the effect of HIF-1α on DNAdamage-induced p53 apoptotic activation by using an ex vivo experimental model consisting of cell populations derived from explants of prostate cancer patients characterized by stabilized HIF-1α protein in normoxia (“constitutively hypoxic” phenotype) and associated with bad prognosis, and cell populations with a phenotype negative for HIF-1α expression under aerobic condition associated with good prognosis [17]

Summary

Introduction

HIPK2 is a potential tumor suppressor gene; it is a nuclear serine/threonine kinase that acts as corepressors for transcription factors [1] and is considered a central switch in the targeting of cells toward apoptosis upon genotoxic stress by phosphorylating tumor suppressor p53 at serine 46 (Ser46) [2,3]. The presence of HIF-1α overexpression at mRNA (Figure 1A) and protein level (see Figure 2F) in C27 cells led to a marked inhibition of drug-induced luciferase activity of the p53AIP1 reporter gene

Results

Conclusion