Defining the mechanisms underlying cyclin dependent kinase control of HIF-1α

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Oncotarget. 2022; 13:454-455. https://doi.org/10.18632/oncotarget.28208

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Noel A. Warfel _


Noel A. Warfel1,2

1 University of Arizona Cancer Center, Tucson, AZ, USA

2 Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA

Correspondence to:

Noel A. Warfel, email: warfelna@arizona.edu

Keywords: hypoxia; HIF-1; cyclin dependent kinase; SMURF2

Received: October 26, 2021     Accepted: February 15, 2022     Published: March 03, 2022

Copyright: © 2022 Warfel. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Commentary on: Zhao and El-Deiry. Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase. Oncotarget. 2021; 12:1970–79. https://doi.org/10.18632/oncotarget.28081. [PubMed]

Constitutive activation of HIF-1α is common in human cancers, regardless of oxygen tension. While the majority of HIF-1 activation can be attributed to lack of oxygen in the tumor microenvironment, numerous non-hypoxic stimuli have also been shown to regulate HIF-1α levels. Stabilization of HIF-1α in normoxia has been attributed to genetic alterations, most notably loss of the von Hippel-Lindau (VHL) tumor suppressor gene, the primary E3 ligase responsible for targeting HIF-1α for proteasomal degradation [1]. In recent years, multiple new proteins and post-translational modifications have been implicated in the oxygen-independent control of HIF-1α. This includes alternative E3-ubiquitin ligases that target HIF-1α for proteasomal degradation (RACK, CHIP, HAF, etc.) [2], as well as binding proteins that enhance stability, such as HSP90 [3]. Another critical event that impacts HIF-1α levels and activation is phosphorylation. Numerous phosphorylation sites and upstream kinases, including PKA and PIM1 kinases, have been identified and shown to modulate HIF-1α protein stability in both normoxia and hypoxia [46]. Regardless of the mechanism, stabilization of HIF-1α in normoxia results in the constitutive upregulation of genes that initiate and sustain signaling pathways that drive cellular processes that support tumor growth and metastasis. As a result, identifying new mechanisms regulating HIF-1 is crucial to our understanding of cancer progression and developing more effective therapies.

Prior research from the El-Deiry lab was the first to demonstrate that the cyclin dependent kinases CDK1 and CDK4/6 are sufficient to stabilize HIF-1α, independent of hypoxia or VHL. Following up on these exciting findings, Zhou and El-Deiry utilized an unbiased proteomic screen to identify SMAD specific E3-ubiquitin protein ligase 2 (SMURF2) as a novel E3 ligase controlling HIF-1α levels downstream of CDK4/6, regardless of oxygen tension. Moreover, mass spectrometry analysis revealed loss of phosphorylation of HIF-1α at Ser451 in cells treated with palbociclib, raising the possibility that this site could be important for maintaining HIF-1 stability. Interestingly, recent work from our group showed that phosphorylation of HIF-1α at Thr455 by PIM1 blocks HIF-1α degradation by disrupting prolyl hydroxylase domain (PHD) protein binding and hydroxylation, which is the initiating step in the canonical HIF-1α degradation pathway [4]. While the mechanism appears to be distinct, since PIM1 blocks VHL-mediated degradation, the close proximity of these sites and their localization within the oxygen dependent degradation domain in HIF-1α points to the importance of post-translational modifications to this region for the regulation of HIF-1α protein stability through both canonical and non-canonical means. Importantly, analysis of the TCGA data showed that high levels of SMURF2 correlated with significantly better overall survival and disease-free survival in clear cell renal cancer, in which over 80% of patients lack functional VHL and display high basal levels of HIF-1α. In a parallel study, the same authors leveraged their findings to test whether targeting multiple molecules that stabilize HIF-1α simultaneously enhanced therapeutic response. Strikingly, the combination of FDA-approved CDK4/6 inhibitors and HSP90 inhibitors showed enhanced inhibition of HIF-1 activity and synergistic anti-tumor effects in models of renal and colon cancer lacking VHL and Rb [7]. Taken together, these studies describe a new mechanism responsible for the activation of HIF-1 in human cancer and provide a strong rationale for the use of CDK4/6 inhibitors to target HIF-1, particularly in tumors lacking VHL or harboring other signaling alterations that promote the constitutive activation of HIF-1.


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