Dataset Information

Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer.

ABSTRACT: Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the ?-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of ?-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554-65. ©2018 AACR.

SUBMITTER: Mao F

PROVIDER: S-EPMC6030429 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer.

Mao Fengyi F Li Jie J Luo Qian Q Wang Ruixin R Kong Yifan Y Carlock Colin C Liu Zian Z Elzey Bennet D BD Liu Xiaoqi X

Molecular cancer therapeutics 20180501 7

Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resultin ...[more]

PMID: 29716963

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Project description:Epigenetic mechanisms involve the placing (writing) or removal (erasing) of histone modifications that allow heterochromatin to transition to the open, activated euchromatin state necessary for transcription. A third, less studied epigenetic pathway involves the reading of these specific histone marks once placed. The BETs (bromodomain and extraterminal-containing protein family), which includes BRD2, BRD3, and BRD4 and the testis-restricted BRDT, are epigenetic reader proteins that bind to specific acetylated lysine residues on histone tails where they facilitate the assembly of transcription complexes including transcription factors and transcriptional machinery like RNA Polymerase II. As reviewed here, considerable recent data establishes BETs as novel determinants of induced transcriptional programs in vascular cells, like endothelial cells and vascular smooth muscle cells, cardiac myocytes and inflammatory cells, like monocyte/macrophages, cellular settings where these epigenetic reader proteins couple proximal stimuli to chromatin, acting at super-enhancer regulatory regions to direct gene expression. BET inhibition, including the use of specific chemical BET inhibitors like JQ-1, has many reported effects in vivo in the cardiovascular setting, like decreasing atherosclerosis, angiogenesis, intimal hyperplasia, pulmonary arterial hypertension, and cardiac hypertrophy. At the same time, data in endothelial cells, adipocytes, and elsewhere suggest BETs also help regulate gene expression under basal conditions. Studies in the cardiovascular setting have highlighted BET action as a means of controlling gene expression in differentiation, cell identity, and cell state transitions, whether physiological or pathological, adaptive, or maladaptive. While distinct BET inhibitors are being pursued as therapies in oncology, a large prospective clinical cardiovascular outcome study investigating the BET inhibitor RVX-208 (now called apabetalone) has already been completed. Independent of this specific agent and this one trial or the numerous unanswered questions that remain, BETs have emerged as novel epigenetic players involved in the execution of coordinated transcriptional programs in cardiovascular health and disease.

Dataset Information

Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer.

Publications

Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer.

Similar Datasets

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