A1 Refereed original research article in a scientific journal
A metabolic prosurvival role for PML in breast cancer
Authors: Carracedo A, Weiss D, Leliaert AK, Bhasin M, de Boer VCJ, Laurent G, Adams AC, Sundvall M, Song SJ, Ito K, Finley LS, Egia A, Libermann T, Gerhart-Hines Z, Puigserver P, Haigis MC, Maratos-Flier E, Richardson AL, Schafer ZT, Pandolfi PP
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Publication year: 2012
Journal: Journal of Clinical Investigation
Journal name in source: JOURNAL OF CLINICAL INVESTIGATION
Journal acronym: J CLIN INVEST
Volume: 122
Issue: 9
First page : 3088
Last page: 3100
Number of pages: 13
ISSN: 0021-9738
DOI: https://doi.org/10.1172/JCI62129
Abstract
Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted. as both a negative regulator of PPAR gamma coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.
Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted. as both a negative regulator of PPAR gamma coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.