Tian Lifeng, Jiao Xuanmao, Wang Chenguang, Li Danni, Ertel Adam, Achinger-Kawecka Joanna, Addya Sankar, Soccio Raymond E, Chen Eric R, Győrffy Balázs, Di Sante Gabriele, Zhong Zhijiu, Alkhafaji Haidar, Entcheva Nina, Campbell Elyssa M, McCue Peter A, Kossenkov Andrew V, Pancsa Rita, Tompa Peter, Clark Susan J, Pestell Richard G
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA.
Oncogene. 2025 Sep;44(37):3476-3492. doi: 10.1038/s41388-025-03492-z. Epub 2025 Jul 26.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）在多种恶性肿瘤中表达，通过转录程序调控生物学功能。明确调控经典与非经典PPARγ结合序列选择的分子机制，可能为设计具有不同功能和副作用的调节剂提供机会。小鼠Pparγ2中K268/293位点的乙酰化参与脂肪组织分化的调控，而小鼠Pparγ1中保守的赖氨酸残基（K154/155）则调控乳腺癌细胞中的脂肪生成。在此，PPARγ1乙酰化残基K154/155被证明对致癌性ErbB2驱动的乳腺癌生长及体内乳腺肿瘤干细胞扩增至关重要。调控生长因子信号传导、脂肪生成、细胞凋亡和干细胞扩增的转录模块的诱导依赖于K154/155。K154/155残基的乙酰化状态决定了全基因组DNA结合位点的选择，改变了从经典到非经典（C/EBP）DNA序列特异性结合的选择。反映脂肪生成中乙酰化依赖性基因组占据情况的基因特征为ErbB2乳腺癌的生存结果提供了预测价值。Pparγ1乙酰化位点对ErbB2诱导的乳腺癌肿瘤生长至关重要，可能代表治疗性共抑制的一个相关靶点。
