Trichostatin A induces bladder cancer cell death via intrinsic apoptosis at the early phase and Sp1-survivin downregulation at the late phase of treatment

Abstract

Histone deacetylase (HDAC) inhibitors have been widely shown to result in cancer cell death. The present study investigated the mechanisms underlying the antitumor effects of the phytochemical trichostatin A (TSA), a classic pan-HDAC inhibitor, in 5,637 urinary bladder cancer cells. It was found that TSA caused cell cycle arrest at the G2/M and G1 phase accompanied by reduced expression of cyclin D1 and upregulated induction of p21. In addition, TSA induced morphological changes, reduced cell viability and apoptotic cell death in 5,637 cells through caspase-3 activation followed by PARP cleavage. The loss of mitochondrial membrane potential (MMP) indicated that TSA induced apoptosis in 5,637 cells through the intrinsic mitochondrial pathway. TSA significantly suppressed Akt activity at 12 h after treatment, suggesting that the apoptosis in the early phase was mediated by Akt inhibition. In addition, the protein level of transcription factor Sp1 was decreased at 24 h after TSA treatment, which likely led to the downregulation of survivin gene expression, and then contributed to the antitumor activity of TSA. Taken together, the present study delineated that TSA-induced growth inhibition and apoptosis in 5,637 cells was associated with pAKT inhibition and MMP loss at the early phase, followed by downregulation of Sp1 and survivin at the late phase of treatment.

NACC1, as a Target of MicroRNA-331-3p, Regulates Cell Proliferation in Urothelial Carcinoma Cells

“…Conventional anticancer drug for UC therapy, such as vinblastine, doxorubicin, and cisplatin act during DNA synthesis and/or various phases of the cell cycle checkpoint, and produce anticancer effects [ 19 ]. There are several reports about anticancer drugs and biological compounds, such as desethylamiodarone [ 20 ], reversine [ 21 ], isoquercitrin [ 22 ], trichostatin A [ 23 ], and miconazole [ 24 ], for chemotherapy of UC. Moreover, the histone deacetylase (HDAC) inhibitor valproic acid (VPA), anticancer agent amygdalin and chalcone, which is a precursor compound for flavonoid synthesis in plants, induced cell growth inhibition via cell cycle arrest at G0/G1 or G2/M phase in UC [ 25 , 26 , 27 ].…”

Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer

“…Cao et al (2015) revealed that the TSA-induced apoptosis in T24 bladder cancer cells is related to TRPM2 (Transient Receptor Potential Cation Channel, Subfamily M, Member 2) upregulation, which is caused by increased H3K9Ac enrichment within the TRPM2 promoter [229]. In another study by Wang et al (2017), TSA administration initially activated the intrinsic apoptotic pathway associated with phosphorylated Akt inhibition and mitochondrial membrane-potential loss, followed by downregulation of the Sp1-Survivin pathway at the late phase of treatment [230]. In vivo TSA administration in mice bearing EJ and UMUC3 bladder cancer xenografts led to a 70% tumor growth suppression and absence of detectable toxicity [227].…”

Teratoma Growth Retardation by HDACi Treatment of the Tumor Embryonal Source

“…TSA is a complete class I and II HDACs inhibitor [26,28], which was originally used as an antimycotic [29]. It increases histone acetylation and consequently has a strong impact on oxidative stress, cell cycle arrest, apoptosis [28,30,31], and epithelial-mesenchymal transition [32].…”