Hyper‐acetylation contributes to the sensitivity of chemo‐resistant prostate cancer cells to histone deacetylase inhibitor Trichostatin A

Abstract

Therapeutic agents are urgently needed for treating metastatic castration‐refractory prostate cancer (mCRPC) that is unresponsive to androgen deprivation and chemotherapy. Our screening assays demonstrated that chemotherapy‐resistant prostate cancer (PCa) cells are more sensitive to HDAC inhibitors than paired sensitive PCa cells, as demonstrated by cell proliferation and apoptosis in vitro and in vivo. Kinetic study revealed that TSA‐induced apoptosis was significantly dependent on enhanced transcription and protein synthesis in an early stage, which subsequently caused ER stress and apoptosis. ChIP analysis indicated that TSA increased H4K16 acetylation, promoting ER stress gene transcription. The changes in Ac‐H4K16, ATF3 and ATF4 were also validated in TSA‐treated animals. Further study revealed the higher enzyme activity of HDACs and an increase in acetylated proteins in resistant cells. The higher nucleocytoplasmic acetyl‐CoA in resistant cells was responsible for elevated acetylation status of protein and a more vigorous growth state. These results strongly support the pre‐clinical application of HDAC inhibitors for treating chemotherapy‐resistant mCRPC.

Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties

“…Docetaxel-resistant PC3/Doc cells are sensitive to AKBA As an initial screening approach, a cell viability assay was carried out to identify the chemicals that potently inhibited cell proliferation in the established docetaxel-resistant PC3/Doc cells ( Fig. 1a) [27,28]. The chemical concentrations that induced cellular death at 50% (IC 50 ) were calculated.…”

“…The docetaxel-resistant cell lines PC3/Doc and RM-1/Doc were selected by growing the PC3 and RM-1 cells in increasing concentrations of docetaxel (Aventis Pharma Dagenham, Dagenham, UK), respectively. The procedure has been described in our previous reports [27,28]. The resistant cells were maintained in medium with 1 nM docetaxel.…”

“…Murine homograft study RM-1 cells from C57BL/6 mouse prostate tumors are androgen independent and commonly used to develop homograft animal models [32]. Here, RM-1 and RM-1/Doc cells were used for the establishment of docetaxel-sensitive and docetaxel-resistant PCa homografts in male C57BL/6 mice, respectively, as described previously [28,30]. For the generation of homotransplantations, 6-week-old male C57BL/6 mice (Vital River Laboratories, Beijing, China) were inoculated subcutaneously in the backs with 1 × 10 5 RM-1 cells in 0.1 mL of physiological saline.…”

HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression

“…A peptide targeting activated α5β1 integrin has been developed, inducing complete regression of intramuscular prostate tumors in mice [ 49 ]. VPA use (in disorders for which a VPA indication exists) has been associated with a decreased cancer risk [ 50 , 51 ], and targeting HDAC is thought to be beneficial in treating prostate cancer, particularly in its advanced state [ 52 , 53 ]. In good accordance with our data, HDAC inhibition suppressed epithelial–mesenchymal plasticity and stemness activity observed in mesenchymal-like tumor cells resistant to Akt-mTOR pathway inhibitors [ 54 ].…”

Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment?

“…Moreover, trichostatin A (TSA), an antifungal antibiotic with pan-HDACi activity is effective in several tumor models at the nanomolar level. TSA inhibits HDAC activity [69], downregulates HDAC1 expression [75], increases histone H4 [69] and estrogen receptor (ER) acetylation in breast cancer cell lines [76], increases histone H3 lysine 9 and lysine 27 acetylation [76] and upregulates p21, p27 and p57 expression in colon cancer cell lines [75] Additionally, in PCa, TSA increases histone H4 lysine 16 acetylation, particularly in CRPC cell lines [73], and affects p53 acetylation [49]. In addition, TSA presents nonepigenetic effects, including decreased cell proliferation [68,74], increased cell death [72,75] with an increase in active caspase-3 levels [71], increased hypoxic responses [74], downregulation of cyclin D1 gene expression [71], cell cycle arrest at G 1 phase, increased expression of Bax gene and downregulated Bcl-2 gene expression and decreased phosphorylation of Akt and ERK proteins [70].…”