ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

Abstract

The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1073/pnas.2210418120

Publication Info

Mayro, Benjamin, Jacob P Hoj, Christian G Cerda-Smith, Haley M Hutchinson, Michael W Caminear, Hannah L Thrash, Peter S Winter, Suzanne E Wardell, et al. (2023). ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1. Proceedings of the National Academy of Sciences of the United States of America, 120(16). p. e2210418120. 10.1073/pnas.2210418120 Retrieved from https://hdl.handle.net/10161/29974.

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Scholars@Duke

Wardell

Suzanne E Wardell

Assistant Research Professor of Pharmacology & Cancer Biology

Throughout my career in science, my work has focused in aspects of steroid hormone (progesterone, estrogen, or androgen) receptor activity in breast and prostate cancers. These interests include not only mechanistic studies of receptor activity in treatment naive tumors, but also the role of these receptors in the evolution of resistance to current therapies.

Despite the development of improved therapies, breast cancer remains a leading cause of mortality in women. While a majority of breast cancers are estrogen receptor (ER) positive and respond to endocrine therapies such as tamoxifen or aromatase inhibitors, as many as 50% of patients experience relapse and progression. Recent data has confirmed continued reliance of these cancers on ER signaling, validating this receptor as a therapeutic target even in a relapsed/metastatic setting. The focus of a majority of my work in breast cancer has been the mechanistic evaluation of methods to target ER activity in this setting of resistance, either through the development of improved receptor antagonists or through the identification of targets downstream of, or impinging upon, ER activity that can serve as secondary targets in this setting. 

Similarly, the androgen receptor (AR) remains a therapeutic target in prostate cancer throughout treatment progression to end stage prostate cancer. Although several AR antagonists have been developed and approved for the treatment of prostate cancer, AR overexpression, as well as mutation and/or truncation, are observed clinically and have been shown mechanistically to render the current AR antagonists ineffective in the advanced prostate cancer setting. As with our work in breast cancer, we have identified pathways downstream of AR that are essential to prostate cancer progression, and our current work is intended to devise treatment regimens that will be effective in lieu of, or together with, AR antagonists.

In my role as a research assistant professor, I have conducted several animal studies evaluating next-to-clinic therapeutics in clinically predictive models of advanced breast and prostate cancer that I have developed throughout the past several years of studies. The entry of some of these therapeutics, or of mechanistically related molecules, into clinical trials in these patient populations validates this approach.

McDonnell

Donald Patrick McDonnell

Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, in the School of Medicine

Lab Website

The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.

Wu

Colleen Wu

Assistant Professor in Orthopaedic Surgery
Wood

Kris Cameron Wood

Associate Professor of Pharmacology and Cancer Biology

Our laboratory uses genomic and pharmacological approaches to understand how tumor dependencies are shaped by cell intrinsic factors, environmental factors, and drug treatments during the dynamic process of tumor evolution. To learn more, please visit our laboratory website: https://woodlabduke.com/.

Pendergast

Ann Marie Pendergast

Anthony R. Means Cancer Biology Distinguished Professor

Research Overview:

Tyrosine Kinase-regulated Transcription Networks in tumor progression to metastasis and the regeneration response to injury.

The long-term goal of our research is to define the role of protein tyrosine kinase-regulated transcription networks in the regulation of cell polarity, growth, survival, differentiation, adhesion, and migration during cancer metastasis and the response to tissue injury. We have a long-standing research interest on the role of protein tyrosine phosphorylation in tumorigenesis. Our early research led to seminal discoveries that defined the critical pathways employed by the BCR-ABL tyrosine kinase to induce human leukemia. We employ animal models and state-of-the art transcriptomic technologies to investigate the role of tyrosine kinase-dependent transcription factor networks during tumor metastasis as well as the regeneration response following lung injury. In particular, we are dissecting the pathways that modulate the crosstalk among multiple cell types during metastasis to the brain. Brain metastases represent the most common adult intracranial malignancy with more than 200,000 patients diagnosed in the U.S. annually. Approximately, 20 to 40% of patients with solid tumors will develop brain metastases and lung cancer patients exhibit the highest prevalence of brain metastasis (40-60%) among all cancer types.  Current therapies to treat brain metastases have proven ineffective due to variable, transient and incomplete responses, as well as inability for drugs to cross the blood-brain-barrier (BBB) to reach therapeutic doses to treat brain metastasis. We have recently reported that ABL tyrosine kinase-driven transcriptional networks promote brain metastasis in mouse models, and found that treatment with ABL allosteric inhibitors impairs brain metastasis in pre-clinical models. Among the research areas currently being pursued in our laboratory are defining the mechanisms that regulate the cross-talk between brain metastatic cells and associated cells in the brain tumor microenvironment. High-level expression of ABL1, ABL2 and a subset of ABL-dependent target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature. The ultimate goal of our studies is to develop novel therapies for the treatment of metastatic solid tumors by targeting not only cancer cells but also associated stromal cells in the tumor microenvironment.

Repair following injury requires dynamic intercellular signaling to promote the proper balance of proliferation and differentiation of specialized epithelial progenitor cell populations required to restore normal lung epithelial architecture and barrier function. Absence or imbalance of these processes may result in death or long-term pulmonary disease among survivors. Currently little is known regarding the identity of signaling networks that might be effectively targeted to promote recovery from lung injury. Unexpectedly we found that inhibition of the ABL kinases promotes lung epithelial regeneration in mice after bacterial pneumonia challenge. Further, pathogen exposure elicits a dramatic increase in Abl1 expression in bronchial epithelial cells. Our exciting data demonstrate that inactivation of ABL kinases in mouse models of bacterial and viral pneumonia promotes alveolar epithelial cell regeneration.

Mentoring Philosophy:

My goal is to train the next generation of scientists and leaders by providing essential skills to develop into independent and creative thinkers. I have extensive experience in training and mentoring students, postdoctoral fellows and junior faculty.  My laboratory provides a collegial and highly interactive environment to promote collaboration and engagement among lab members and colleagues across the University. We conduct weekly laboratory research and journal club meetings, and weekly one-on-one meetings with trainees to discuss research progress, trouble shooting, planning future research, and writing publications and grants. Lab trainees have gone to successful academic careers and are currently Professors, Associate and Assistant Professors at various academic institutions. I have also trained outstanding post-doctoral fellows who have gone to successful research careers in industry.

 


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