Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:15135-15149. https://doi.org/10.18632/oncotarget.7715

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Abstract

Xiaokun Gang1,2,*, Yinhui Yang2,3,*, Jian Zhong2, Kui Jiang2,4, Yunqian Pan2, R. Jeffrey Karnes5, Jun Zhang6, Wanhai Xu3, Guixia Wang1, Haojie Huang2,5,7

1Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, China

2Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

3Department of Urology, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China

4Department of Oncology, The Second affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, China

5Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

6Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

7Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

*These authors have contributed equally to this work

Correspondence to:

Wanhai Xu, e-mail: [email protected]

Guixia Wang, e-mail: [email protected]

Haojie Huang, e-mail: [email protected]

Keywords: P300, FASN, histone acetylation, lipid metabolism, prostate cancer

Received: January 24, 2016     Accepted: January 30, 2016     Published: February 25, 2016

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.


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