P110β Inhibition Reduces Histone H3K4 Di‐Methylation in Prostate Cancer. Issue 3 (1st November 2016)

• Record Type: Journal Article
• Authors: Pang, Jun; Yang, Yue‐Wu; Huang, Yiling; Yang, Jun; Zhang, Hao; Chen, Ruibao; Dong, Liang; Huang, Yan; Wang, Dongying; Liu, Jihong; Li, Benyi
• Is Part Of: Prostate. Volume 77:Issue 3(2017)
• Page Start: 299
• Page End: 308
• Publication Date: 2016-11-01
• Subjects: histone methylation -- prostate cancer -- androgen -- PI3K -- AKT -- p110beta; Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.23271
• Languages: English
• ISSNs: 0270-4137

Abstract

Abstract : INTRODUCTION AND AIMS: Epigenetic alteration plays a major role in the development and progression of human cancers, including prostate cancer. Histones are the key factors in modulating gene accessibility to transcription factors and post‐translational modification of the histone N‐terminal tail including methylation is associated with either transcriptional activation (H3K4me2) or repression (H3K9me3). Furthermore, phosphoinositide 3‐kinase (PI3 K) signaling and the androgen receptor (AR) are the key determinants in prostate cancer development and progression. We recently showed that prostate‐targeted nano‐micelles loaded with PI3 K/p110beta specific inhibitor TGX221 blocked prostate cancer growth in vitro and in vivo. Our objective of this study was to determine the role of PI3 K signaling in histone methylation in prostate cancer, with emphasis on histone H3K4 methylation. METHODS: PI3 K non‐specific inhibitor LY294002 and p110beta‐specific inhibitor TGX221 were used to block PI3 K/p110beta signaling. The global levels of H3K4 and H3K9 methylation in prostate cancer cells and tissue specimens were evaluated by Western blot assay and immunohistochemical staining. A synthetic androgen R1881 was used to stimulate AR activity in prostate cancer cells. A castration‐resistant prostate cancer (CRPC) specific human tissue microarray (TMA) was used to assess the global levels of H3K4me2 methylation by immunostaining approach. RESULTS: Our data revealed that H3K4me2 levels were significantly elevated after androgen stimulation. With RNA silencing and pharmacology approaches, we further defined that inhibition of PI3 K/p110beta activity through gene‐specific knocking down and small chemical inhibitor TGX221 abolished androgen‐stimulated H3K4me2 methylation. Consistently, prostate cancer‐targeted delivery of TGX221 in vivo dramatically reduced the global levels of H3K4me2 as assessed by immunohistochemical staining on tissue section of mouse xenografts from CRPC cell lines 22RV1 and C4‐2. Finally, immunostaining data revealed a strong H3K4me2 immunosignal in CRPC tissues compared to primary tumors and benign prostate tissues. CONCLUSIONS: Taken together, our results suggest that PI3 K/p110beta‐dependent signaling is involved in androgen‐stimulated H3K4me2 methylation in prostate cancer, which might be used as a novel biomarker for disease prognosis and targeted therapy. Prostate 77:299–308, 2017 . © 2016 Wiley Periodicals, Inc.