The histone deacetylase inhibitor panobinostat exerts anticancer effects on esophageal squamous cell carcinoma cells by inducing cell cycle arrest

Abstract

Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Histone deacetylase inhibitors (HDACIs) have been demonstrated as an emerging class of anticancer drugs for a range of haematological and solid tumours. However, the effect of HDACIs has not yet been investigated on ESCC cells. In this study, HDACIs were initially considered to have anticancer activity for ESCC, due to the high expression of HDAC genes in ESCC cell lines by analysing expression data of 27 ESCC cell lines from the Broad‐Novartis Cancer Cell Line Encyclopedia. Next, we used five ESCC cell lines and one normal immortalized esophageal epithelial cell line to screen three HDACIs, panobinostat (LBH589), vorinostat (SAHA), and trichostatin A (TSA), for the ability to inhibit growth. Here, we report that LBH589 more effectively suppressed cell proliferation of ESCC cell lines, in a dose‐dependent manner, than TSA and SAHA, as well as had lower toxicity against the SHEE normal immortalized esophageal epithelial cell line. Further experiments indicated that LBH589 treatment significantly inhibited TP53 (mutated TP53) expression, both at the mRNA and protein level, and simultaneously increased p21 and decreased cyclin D1 expression. Taken together, we propose that LBH589 inhibits ESCC cell proliferation mainly through inducing cell cycle arrest by increasing p21 and decreasing cyclin D1 in a p53‐independent manner. Significance of the study In this study, the antitumor activity of HDACIs LBH589, SAHA, and TSA on ESCC was characterized, with LBH589 displaying the most potent anti‐proliferative activity while not harming normal immortalized esophageal epithelial cells. Furthermore, we propose that LBH589 exerts its anti‐proliferative effect by inducing cell cycle arrest. The ability to specifically target cancer cells indicates therapeutic potential for use of LBH589 in the treatment of ESCC.

Overexpression of KIAA0101 Promotes the Progression of Non-small Cell Lung Cancer

“…These proteins tightly control the cell cycle progression, with critical roles in DNA replication and mitosis. On the other hand, they are also important downstream factors in the TP53 pathway [19]. Lv et al reported the network of KIAA0101, TP53, SP1 functioned in breast cancer, and the depletion of KIAA0101 suppressed cell cycle progression.…”

Establishment of prognostic risk model and drug sensitivity based on prognostic related genes of esophageal cancer

“…Our study found that the high expression of hist1h1e was more sensitive to tubastatin A, vorinostat, CAY 10603, AR-42, I-BET-762, NPK76-II-72-1, Genentech Cpd 10, navitoclax, PIK-93, PI-103, PHA-793887, WZ3105 and TPCA-1, but resistant to trametinib, selumetinib, rdea119, docetaxel and 17-AAG. Tubastatin A 34 , vorinostat 35 , AR-42 36 and navitoclax (ABT-263) 37 all reported inhibitory effects on the proliferation of esophageal cancer cells. It is speculated that the high expression of HIST1H1E may play a role in drug sensitivity and drug action.…”

Progenitor cells derived from gene‐engineered human induced pluripotent stem cells as synthetic cancer cell alternatives for in vitro pharmacology

“…Previously, a molecular link of vinblastine exposure and cellular transcriptional activation of TP53 has been reported, but no association to resistance in oncogenic loss of function of wild‐type TP53 has been investigated 35 . Interestingly, panobinostat was reported to block the transcription/translation of mutant TP53 in esophageal squamous cancer 36 and preferentially reduces resistance to EGFR inhibitor treatment in lung cancer independent of EFGR mutation status 37 . As a study in the context of colon cancer previously showed, the therapeutic potential of pharmacological HDAC inhibition (HDACi) is dependent on the TP53 mutation status of cancers and varies from the agent applied, however, no specific tests with panobinostat have been reported 38 .…”