P300 acetyltransferase regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth

Xiaokun Gang, Yinhui Yang, Jian Zhong, Kui Jiang, Yunqian Pan, R. Jeffrey Karnes, Jun Zhang, Wanhai Xu, Guixia Wang, Haojie Huang

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15135-15149
Number of pages15
JournalOncotarget
Volume7
Issue number12
DOIs
StatePublished - Mar 22 2016

Keywords

  • FASN
  • Histone acetylation
  • Lipid metabolism
  • P300
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

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