PPARγ acetylation governs mammary adenocarcinoma tumor growth via acetylated residues that determine DNA sequence-specific binding
Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Defining the molecular mechanisms governing the selection of canonical versus non-canonical PPARγ binding sequences may provide the opportunity to design regulators with distinct functions and side effects. Acetylation at K268/293 in mouse Pparγ2 participates in the regulation of adipose tissue differentiation, and the conserved lysine residues (K154/155) in mouse Pparγ1 governs lipogenesis in breast cancer cells. Herein, the PPARγ1 acetylated residues K154/155 were shown to be essential for oncogenic ErbB2 driven breast cancer growth and mammary tumor stem cell expansion in vivo. The induction of transcriptional modules governing growth factor signaling, lipogenesis, cellular apoptosis, and stem cell expansion were dependent upon K154/155. The acetylation status of the K154/155 residues determined the selection of genome-wide DNA binding sites, altering the selection from canonical to non-canonical (C/EBP) DNA sequence-specific binding. The gene signature reflecting the acetylation-dependent genomic occupancy in lipogenesis provided predictive value in survival outcomes of ErbB2<sup>+</sup> breast cancer. The Pparγ1 acetylation site is critical for ErbB2-induced breast cancer tumor growth and may represent a relevant target for therapeutic coextinction.
Authors
- Adam Ertel (ORCID: https://orcid.org/0000-0001-7455-1559)
- Péter Tompa (ORCID: https://orcid.org/0000-0001-8042-9939)
- Peter A. McCue (ORCID: https://orcid.org/0000-0001-9806-0594)
- Andrew V. Kossenkov (ORCID: https://orcid.org/0000-0002-1536-0418)
- Richard G. Pestell (ORCID: https://orcid.org/0000-0003-3244-8777)
- Balázs Győrffy (ORCID: https://orcid.org/0000-0002-5772-3766)
- Xuanmao Jiao (ORCID: https://orcid.org/0000-0003-4222-9172)
- Joanna Achinger-Kawecka (ORCID: https://orcid.org/0000-0002-2902-9371)
- Susan J. Clark (ORCID: https://orcid.org/0000-0001-5925-5030)
- Zhijiu Zhong (ORCID: https://orcid.org/0000-0001-9828-298X)
- Elyssa Campbell (ORCID: https://orcid.org/0000-0001-9198-7290)
- Raymond E. Soccio (ORCID: https://orcid.org/0000-0001-8863-1381)
- Rita Pancsa (ORCID: https://orcid.org/0000-0003-0849-9312)
- Eric R. Chen (ORCID: https://orcid.org/0000-0002-6712-9488)
- Lifeng Tian (ORCID: https://orcid.org/0000-0001-9740-5327)
- Gabriele Di Sante (ORCID: https://orcid.org/0000-0001-6608-3388)
- Chenguang Wang (ORCID: https://orcid.org/0000-0002-9082-2117)
- Danni Li (ORCID: https://orcid.org/0000-0002-8151-2803)
- Sankar Addya
- Haidar Alkhafaji (ORCID: https://orcid.org/0009-0006-5771-2449)
- Nina Entcheva
Institutions
- Semmelweis University (HU)
- The Wistar Institute (US)
- University of Debrecen (HU)
- Children's Hospital of Philadelphia (US)
- Garvan Institute of Medical Research (AU)
- Thomas Jefferson University (US)
- University of Aruba (AW)
- Sidney Kimmel Cancer Center (US)
- National Institute of Oncology (HU)
- Baruch S. Blumberg Institute (US)
- University of Pennsylvania (US)
- University of Pecs (HU)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Oncogene
- Published
- 2025-07-26
- DOI
- https://doi.org/10.1038/s41388-025-03492-z
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Magyar Tudományos Akadémia
- National Institutes of Health
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
- National Research, Development and Innovation Office