Tian, Lifeng and Jiao, Xuanmao and Wang, Chenguang and Li, Danni and Ertel, Adam and Achinger-Kawecka, Joanna and Addya, Sankar and Soccio, Raymond E. and Chen, Eric R. and Győrffy, Balázs and Di, Sante Gabriele and Zhong, Zhijiu and Alkhafaji, Haidar and Entcheva, Nina and Campbell, Elyssa M. and McCue, Peter A. and Kossenkov, Andrew V. and Pancsa, Rita and Tompa, Péter and Clark, Susan and Pestell, Richard George (2025) PPARγ acetylation governs mammary adenocarcinoma tumor growth via acetylated residues that determine DNA sequence-specific binding. ONCOGENE, 44. pp. 3476-3492. ISSN 0950-9232
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Abstract
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+ breast cancer. The Pparγ1 acetylation site is critical for ErbB2-induced breast cancer tumor growth and may represent a relevant target for therapeutic coextinction.
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| Additional Information: | Funding Agency and Grant Number: U.S. Department of Health & Human Services | National Institutes of Health (NIH) [R01CA132115, R21CA235139-01, R43HL164131]; NIH [W81XWH1810605, W81XWH-22-BRCP]; DOD Breast Cancer Research Program Breakthrough Awards [RGH_24 (RGH 151464)]; National Research, Development and Innovation Fund of the Ministry of Culture and Innovation [NVKP_16-1-2016-0037]; National Research, Development and Innovation Office (RGP) [BO/00174/22]; National Research, Development and Innovation Office, Hungary; Hungarian Academy of Sciences Funding text: RGP was supported in part by NIH R01CA132115, R21CA235139-01, and R43HL164131, and the DOD Breast Cancer Research Program Breakthrough Awards (W81XWH1810605, and W81XWH-22-BRCP). The project was implemented with the support from the National Research, Development and Innovation Fund of the Ministry of Culture and Innovation under the RGH_24 (RGH 151464) Grant Agreement with the National Research, Development and Innovation Office (RGP). BG was supported by the NVKP_16-1-2016-0037 grant of the National Research, Development and Innovation Office, Hungary. RP was supported by the FK-142285 grant of the National Research, Development and Innovation Office, Hungary. RP is a holder of the Bolyai Fellowship (BO/00174/22) from the Hungarian Academy of Sciences. There are no conflicts of interest associated with this manuscript. |
| Subjects: | R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 16 Sep 2025 09:08 |
| Last Modified: | 16 Sep 2025 09:08 |
| URI: | https://real.mtak.hu/id/eprint/224323 |
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