1. Panobinostat reverses HepaCAM gene expression and suppresses proliferation by increasing histone acetylation in prostate cancer.
- Author
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Chen E, Liu N, Zhao Y, Tang M, Ou L, Wu X, and Luo C
- Subjects
- Androgen Antagonists pharmacology, Apoptosis drug effects, Cell Cycle drug effects, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Proliferation drug effects, China, Epigenesis, Genetic drug effects, Gene Expression drug effects, Gene Expression Regulation drug effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases genetics, Histone Deacetylases metabolism, Histones metabolism, Humans, Male, Panobinostat metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Receptors, Androgen, Signal Transduction drug effects, Cell Cycle Proteins genetics, Panobinostat pharmacology, Prostatic Neoplasms genetics
- Abstract
Increased expression of histone deacetylases (HDACs) affiliated to the epigenetic regulation is common aberration in prostate cancer (PCa). We have confirmed that hepatocyte cell adhesion molecule (hepaCAM), acting as a tumor suppressor gene, is rarely expressed in PCa previously, However, the mechanisms of which is still unknown. The level of histone acetylation reportedly may involve anti-oncogene transcription and expression. In this study, we investigated the effect of panobinostat, the broad-spectrum histone deacetylases inhibitor, on PCa LNCaP and DU145 cell growth, and observed re-expression of hepaCAM when treated with panobinostat. We demonstrated that intranuclear acetylation of lys9 of histone H3 (Ac-H3K9) were increased, while that of both mRNA and protein of HDAC1, HDAC3, and HDAC4 were decreased when the treating concentration of panobinostat increased. We confirmed the relationship between histone acetylation and the expression of hepaCAM and AR in prostate cancer tissues. We also confirmed that panobinostat could overcome the resistance for androgen deprivation therapy (ADT). Further, we combined panobinostat with Ad-hepaCAM, which resulted in significantly increased antitumor activity and significant attenuation of the proliferation-associated genes CCND1 and PCNA compared to each single treatment. In conclusion, panobinostat may enhance the acetylation of lys9 of histone 3 and reverse the hepaCAM expression through its inhibitory effect on HDACs activity in PCa LNCaP and DU145 cells; Ad-hepaCAM combined with panobinostat may synergistically inhibit the growth of LNCaP and DU145 cells, via a potential mechanism associated with the down-regulation of the expression of CCND1 and PCNA. These findings suggest that this therapeutic strategy should be further developed in clinical trials., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2022
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