Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms
- University of California, San Francisco, United States
- Harvard Medical School, United States
- University of Washington, United States
- Cornell University, United States
Abstract
Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components, and an Aurora Kinase A (AURKA) /glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar liver cancer (FLC) line that expresses a DNAJ-PKAc fusion, and a PKA-addicted melanoma model with a mutant Type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Mass spectrometry RAW mass spectrum files have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD025508.
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TCGA pan-cancer atlasTCGA pan-cancer atlas / NA.
Article and author information
Author details
Funding
Fibrolamellar Cancer Foundation (N/A)
- John D Gordan
Burroughs Wellcome Fund Career Award (N/A)
- John D Gordan
Fibrolamellar Cancer Foundation (N/A)
- Nabeel Bardeesy
Fibrolamellar Cancer Foundation (N/A)
- John D Scott
National Institutes of Health (DK119192)
- John D Scott
DOD Peer Reviewed Cancer Research Program (12715138)
- Raymond S Yeung
National Institutes of Health (F32CA239333)
- Mehdi Bouhaddou
National Institutes of Health (U54 CA209891)
- Nevan J Krogan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ivan Topisirovic, Jewish General Hospital, Canada
Ethics
Human subjects: Human FLCs and paired normal livers were obtained from the University of Washington Medical Center and Seattle Children's Hospital after institutional review board approval (SCH IRB #15277). For prospective fresh tissue collections, informed consent was obtained from the subject and/or parent prior to resection.
Version history
- Preprint posted: April 16, 2021 (view preprint)
- Received: April 17, 2021
- Accepted: January 22, 2023
- Accepted Manuscript published: January 24, 2023 (version 1)
- Version of Record published: February 13, 2023 (version 2)
- Version of Record updated: September 8, 2023 (version 3)
Copyright
© 2023, Chan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms
eLife 12:e69521.
https://doi.org/10.7554/eLife.69521
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
