Overexpression of HDAC9 promotes oral squamous cell carcinoma growth, regulates cell cycle progression, and inhibits apoptosis

Abstract

Histone deacetylases (HDACs) are a family of deacetylase enzymes that regulate the acetylation state of histones and a variety of other non-histone proteins including key oncogenic and tumor suppressor proteins, which modulates chromatin conformation, leading to regulation of gene expression. HDACs has been grouped into classes I-IV and histone deacetylase 9 (HDAC9) belongs to class IIa which exhibits tissue-specific expression. Recent reports have demonstrated both pro-oncogenic and tumor suppressive role for HDAC9 in different cancers; however, its role in OSCC remains elusive. Here, we investigated the role of HDAC9 in pathogenesis of oral squamous cell carcinoma (OSCC). Our data showed significantly increased mRNA and protein expression of HDAC9 in clinical OSCC samples and UPCI-SCC-116 cells as compared to normal counterpart. Kaplan-Meier analysis showed that the patients with high-level of HDAC9 expression had significantly reduced overall survival than those with low-level of HDAC9 expression (p = 0.034). Knockdown of HDAC9 using siRNA interference suppressed cell proliferation, increased apoptosis, and induced G0/G1 cell cycle arrest in UPCI-SCC-116 cells. Immunofluorescence analysis showed increased nuclear localization of HDAC9 in frozen OSCC sections, and indicative of active HDAC9 that may transcriptionally repress its downstream target genes. Subsequent investigation revealed that overexpression of HDAC9 contributes to OSCC carcinogenesis via targeting a transcription factor, MEF2D, and NR4A1/Nur77, a pro-apoptotic MEF2 target.

MicroRNA‑101‑3p inhibits proliferation in retinoblastoma cells by targeting EZH2 and HDAC9

“…Previous studies have also reported the expression and functional roles of HDAC9 in various types of cancer. Upregulated expression of HDAC9 was identified to promote oral squamous cell carcinoma growth and cell cycle progression through targeting of the transcription factors myocyte enhancer factor 2D and nuclear receptor subfamily 4 group A member 1 (37). Additionally, a study by Zhao et al (38) demonstrated that HDAC9 epigenetically repressed the transcription of p53 via binding to its proximal promoter region, thus enhancing the proliferation of osteosarcoma 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, ).…”

High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma

“…Therefore, Hdacs are potential therapeutic targets for some neoplasms. Previous studies have demonstrated that Hdac inhibitors can induce cell cycle arrest, apoptosis and tumor cell differentiation (9,10). Several Hdac inhibitors have been studied in patients with solid neoplasms or other malignancies, and are considered potential anticancer drug candidates (11,12).…”