Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Abstract

The overexpression of histone deacetylases (HDACs) has been observed in many cancers and inhibition of specific HDAC has emerged as a new target for cancer therapy. The present study examined the expression of HDAC8 and the inhibitory effect of HDAC8 in oral squamous cell carcinoma (OSCC). The expression of HDAC8 was measured in human OSCC tissues and OSCC cell lines using immunohistochemistry and immunoblotting. HDAC8 was knocked down in OSCC cells by transfection with HDAC8 siRNAs and cell proliferation was quantified. Apoptosis and autophagy were measured using flow cytometry and immunoblotting. HDAC8 were overexpressed in OSCC tissues and OSCC cells, mainly localized in the cytoplasm. HDAC8 siRNAs effectively reduced the level of HDAC8 expression and HDAC8 silencing significantly inhibited the proliferation of OSCC cells. HDAC8 knockdown induced apoptotic cell death through caspases activation and pro-survival autophagy in OSCC cells. Combination with HDAC silencing and autophagy inhibition enhanced cell death by increasing apoptosis in OSCC cells. This study suggests that inhibition of HDAC8 might become a novel therapeutic strategy for OSCC.

Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

“…It is found that knockdown of HDAC8 promotes autophagy which relates to the inhibition of growth in oral cancer cells [43]. We found that autophagy is an early response after the treatment of HMC for 6 h in MCF-7 cells.…”

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

“…Histone deacetylases (HDACs) promote transcriptional repression and gene silencing by creating the non‐permissive chromatin. HDAC1 (Kumar, Yadav, Lang, Teknos, & Kumar, ; Theocharis et al, ), HDAC2 (Chang et al, ; Theocharis et al, ), HDAC6 (Sakuma et al, ), HDAC8 (Ahn & Yoon, ), and HDAC9 (Rastogi et al, ) were upregulated in OSCC tissues and associated with advanced stages (Chang et al, ; Sakuma et al, ), reduced OS (Chang et al, ; Rastogi et al, ; Theocharis et al, ), and poor prognosis (Chang et al, ). Specifically, HDAC1 overexpression demonstrated correlations with younger age, male gender, poor differentiation, shorter DFS, and metastases (Theocharis et al, ), and high HDAC2 abundance was associated with advanced T and N status (Chang et al, ).…”

“…HDAC2 boosted cell invasion and migration and regulated tumorigenesis and progression in mice (Chang et al, ). Overexpression of HDACs were found in HNSCC cell lines as well (Ahn & Yoon, ; Kumar et al, ; Rastogi et al, ; Sakuma et al, ). Sir2 homolog SIRT1 expression and catalytic activity were both elevated in OSCC cells (Xiong, Li, Tang, & Chen, ).…”

“…Sir2 homolog SIRT1 expression and catalytic activity were both elevated in OSCC cells (Xiong, Li, Tang, & Chen, ). HDACs‐depleted OSCC cells induced apoptosis through caspases activation and pro‐survival autophagy (Ahn & Yoon, ), repressed invasion and metastasis (Chang et al, ), and may halt G0/G1 cell cycle progression by binding non‐histone substrates transcription factor myocyte enhancer factor 2D and repressing orphan nuclear receptor NR4A1 transcription (Rastogi et al, ).…”

RNA interference: new mechanistic and biochemical insights with application in oral cancer therapy

“…By targeting HDAC8 with siRNA, the expression of this enzyme was reduced, leading to reduced proliferation and increased apoptosis within the cells. 74 After silencing the Frmd4A gene, the CAL 27 cells remained in the G0 phase with impaired proliferative, invasive, and migration capacities. 75 Molecular analysis showed that a number of genes were affected by the treatment and that these genes were involved in the cell cycle, in the following signaling pathways: JAK/ STAT, p53, and extracellular matrix proteins.…”