Suberoylanilide hydroxamic acid (SAHA) reverses chemoresistance in head and neck cancer cells by targeting cancer stem cells via the downregulation of nanog.

Bhavna Kumar,James C Lang,Theodoros N Teknos,Pawan Kumar,Arti Yadav

doi:10.18632/genesandcancer.54

Abstract

Acquisition of chemoresistance and metastatic phenotype are the major causes of treatment failure and mortality in head and neck squamous cell carcinoma (HNSCC) patients. Histone deacetylases (HDACs) have been shown to be overexpressed in many tumor types and directly linked to poor prognosis. In this study, we demonstrate that HDACs are markedly elevated in HNSCC. HDACs expression was further increase in cisplatin resistant cell lines (CisR). In addition, cisplatin-resistant cells showed enhanced stem cell properties and tumor metastasis. Depletion of HDAC1 and 2 in CisR cell lines significantly reversed cisplatin resistance and tumorsphere formation. Next, we tested the efficacy of Suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, by using both in vitro and in vivo models. SAHA significantly inhibited cell proliferation and synergistically enhanced the anti-proliferative effects of cisplatin. In addition, SAHA significantly decreased tumorsphere formation by markedly reducing nanog expression. In a SCID mouse xenograft model, SAHA significantly enhanced the anti-tumor effects of cisplatin treatment with no added systemic toxicity. Furthermore, SAHA and cisplatin combination treatment significantly decreased tumor metastasis and nanog expression, in vivo. Taken together, our results suggest that targeting HDACs with SAHA could be an effective treatment strategy for the treatment of HNSCC patients.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the 8th leading cancer worldwide with almost 650,000 new cases diagnosed every year and 350,000 cancerrelated deaths annually [1,2,3]
Our results show that HDAC1 expression is significantly higher (Mann-Whitney test; p = 0.0262) in head and neck tumors as compared to adjacent normal control tissues (Fig. 1A)
We examined HDAC1, HDAC2 and HDAC6 levels in 8 head and neck cancer cell lines and normal human oral keratinocytes (HOK)

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the 8th leading cancer worldwide with almost 650,000 new cases diagnosed every year and 350,000 cancerrelated deaths annually [1,2,3]. Advancements in the anti-cancer treatments including surgery, radiation and chemotherapy have increased the local control of HNSCC, the overall survival rates have not improved significantly over the last three decades [4, 5]. Five year survival rates for patients with early stage localized head and neck cancers are more that 80% but drop to 40% when the disease has spread to the neck nodes, and to below 20%. It is important to understand the molecular mechanisms that contribute to drug resistance in order to identify novel therapeutic targets for head and neck cancer

Methods

Results

Conclusion