De novo fatty acid (FA) synthesis is required for prostate cancer (PCa) survival and progression. As a key enzyme for FA synthesis fatty acid synthase (FASN) is often overexpressed in human prostate cancers and its expression correlates with worse prognosis and poor survival. P300 is an acetyltransferase that acts as a transcription co-activator. Increasing evidence suggests that P300 is a major PCa promoter, although the underlying mechanism remains poorly understood. Here, we demonstrated that P300 binds to and increases histone H3 lysine 27 acetylation (H3K27Ac) in the FASN gene promoter. We provided evidence that P300 transcriptionally upregulates FASN expression and promotes lipid accumulation in human PCa cells in culture and Pten knockout prostate tumors in mice. Pharmacological inhibition of P300 decreased FASN expression and lipid droplet accumulation in PCa cells. Immunohistochemistry analysis revealed that expression of P300 protein positively correlates with FASN protein levels in a cohort of human PCa specimens. We further showed that FASN is a key mediator of P300-induced growth of PCa cells in culture and in mice. Together, our findings demonstrate P300 as a key factor that regulates FASN expression, lipid accumulation and cell growth in PCa. They also suggest that this regulatory pathway can serve as a new therapeutic target for PCa treatment.
[1]Jilin Univ, Hosp 1, Dept Endocrinol & Metab, Changchun 130021, Jilin, Peoples R China.
[2]Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA.
[3]Harbin Med Univ, Hosp 4, Dept Urol, Harbin 150001, Heilongjiang, Peoples R China.
[4]Dalian Med Univ, Affiliated Hosp 2, Dept Oncol, Dalian 116027, Liaoning, Peoples R China.
[5]Mayo Clin, Coll Med, Dept Urol, Rochester, MN 55905 USA.
[6]Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA.
[7]Mayo Clin, Coll Med, Ctr Canc, Rochester, MN 55905 USA.
(8.0+极速模式)