The HDAC inhibitor, panobinostat, induces apoptosis by suppressing the expresssion of specificity protein 1 in oral squamous cell carcinoma

Abstract

Inhibitors of histone deacetylases (HDACs) represent a novel class of therapeutic anticancer agents. Panobinostat (LBH589) induces apoptosis through the regulation of specificity protein 1 (Sp1) in the oral squamous cell carcinoma (OSCC) cell lines, HN22 and HSC4. In this study, we analyzed the underlying signaling pathways and the mechanisms involved in this process by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, 4' ,6-diamidino-2-phenylindole (DAPI) staining, immunocytochemistry and western blot analysis. LBH589 significantly reduced cell growth and the sub-G1 cell population and induced apoptosis. Sp1 protein expression was significantly reduced following treatment with LBH589 in a concentration-dependent manner. Furthermore, LBH589 upregulated the expression of p27 and p21 and downregulated the expression of cyclin D1, myeloid cell leukemia-1 (Mcl-1) and survivin; this led to the activation of apoptotic signaling pathways through the increase of Bax expression and the decrease of Bid and Bcl-xL expression. Treatment with LBH589 also induced the cleavage of caspase-3 and PARP in the HN22 and HSC4 cells. Taken together, our data demonstrate that LBH589 induces the apoptosis of OSCC cells by suppressing Sp1 expression, indicating that LBH589 may be a promising chemotherapeutic agent for the treatment of OSCC.

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

“…In addition to modifying histone acetylation status, HDACs have numerous other nonhistone targets, including proteins involved in transcription regulation, cell proliferation, metabolism, apoptosis, and immune response (70). HDAC inhibitors have been shown to alter the expression level and function of cellular proteins p21, E2F1, and SP1 (71)(72)(73)(74), all of which can impact upon optimal viral gene expression and growth. The transcription factors E2F1 and SP1 both play a role in transcriptional control of E1A (75,76).…”

Licochalcone A, a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma

“…In this study, treatment of OSCC cells (HN22 and HSC4) with LCA decreased significantly expression of Sp1 protein in a dose-and time-dependent manner. To further strengthen the effect of LCA on Sp1, we scrutinized expression of Sp1 target proteins such as p21, p27, cyclin D1, Mcl-1 and survivin (9,33,34). The promoter of Sp1 target proteins contains frequent GC-rich sequences and can be regulated by Sp1 protein (35)(36)(37).…”

“…In spite of the efforts made to investigate many natural products to find effective chemicals for oral cancers over the last several decades (9), there are currently limited options to treat oral cancer. Even though the frequency of oral cancer is low, the need for effective and selective natural products is increasing.…”

Anti‐Proliferative Properties of Kahweol in Oral Squamous Cancer Through the Regulation Specificity Protein 1

“…Therefore, Sp1 might be a good therapeutic molecular target as well as a potential predictor of poor prognosis in cancers. Previous studies found that Sp1 was enhanced in OSCCs, and the downregulation of Sp1 played a role in growth inhibition and induction of apoptosis in oral cancer cells and malignant pleural mesothelioma Jeon et al, 2013;Kim et al, 2013). Also, it was reported that many tumorrelated genes including Bvl-xl, survivin, Bax, and caspase-3 contain Sp1 sites in their promoter region (Black et al, 2001).…”