Targeting HDAC/OAZ1 axis with a novel inhibitor effectively reverses cisplatin resistance in non-small cell lung cancer

Yuhong Sun,Lina Jia,Chunfu Wu,Shenglan Zou,Guoliang Chen,Yong Ren,Qixiang Hua,Jian Han,Hong Li,Lihui Wang,Mengyue Zhao,Xuefei Bao,Yi Fang,Mei Han,Jingyu Yang

doi:10.1038/s41419-019-1597-y

Abstract

Cisplatin yields significant efficacy and is generally used as a frontline therapy for non-small cell lung cancer (NSCLC). However, acquired resistance strongly limits its application. Here, we identified that a novel histone deacetylase (HDAC) inhibitor S11, with P-glycoprotein inhibitory activity, could obviously suppress cell growth in cisplatin-resistant NSCLC cell lines. In addition, S11 could increase the expression of Ac-H4 and p21, which confirmed its HDAC inhibitory action, suppress colony formation, and block cell migration of cisplatin-resistant NSCLC cells. Notably, co-treatment with S11 and cisplatin exhibited synergistically inhibitory efficacy in cisplatin-resistant NSCLC cells. Gene microarray data showed that OAZ1 was downregulated in resistant cells but upregulated after S11 treatment. Further study indicated that knockdown of OAZ1 by siRNA resulted in the decrease of sensitivity of resistant cells to cisplatin treatment and contributed to the increase of resistant cell migration. Additionally, ChIP assay data demonstrated that HDAC inhibitor S11 could increase the accumulation of Ac-H4 in OAZ1 promoter region, suggesting the direct regulation of OAZ1 by HDAC. Importantly, the combination of S11 and cisplatin overcome resistance through inhibiting HDAC activity and subsequently increasing the OAZ1 expression in preclinical model. Moreover, we observed that positive expression of HDAC1 was associated with the downregulation of OAZ1 in NSCLC patients with platinum-based treatment, and predicted drug resistance and poor prognosis. In summary, we demonstrated a role of HDAC/OAZ1 axis in cisplatin-resistant NSCLC and identified a promising compound to overcome cisplatin resistance.

Highlights

Non-small cell lung cancer (NSCLC) is considered as one of the main cause of cancer-related death worldwide[1]
Our previous study showed that continuous treatment with cisplatin resulted in the activation of histone deacetylase (HDAC), which might contribute to the accumulation of cancer stem cells and drug resistance, and the combination of HDAC inhibitor and cisplatin could synergistically inhibit tumor growth in NSCLC model[7], suggesting HDAC inhibition might be the approach to block the development of cisplatin resistance
Cisplatin-based chemotherapeutics are widely used against NSCLC; preventing or blocking cisplatin resistance is considered as a crucial clinical issue in the treatment of NSCLC3

Summary

Introduction

Non-small cell lung cancer (NSCLC) is considered as one of the main cause of cancer-related death worldwide[1]. Several recent studies have elucidated that HDAC inhibitors could exhibit synergistic therapeutic effects when combined with some anti-cancer agents, including DNAdamaging agents, taxanes, targeted agents, and hormonal therapies[13,14,15,16]. Our previous study showed that continuous treatment with cisplatin resulted in the activation of HDAC, which might contribute to the accumulation of cancer stem cells and drug resistance, and the combination of HDAC inhibitor and cisplatin could synergistically inhibit tumor growth in NSCLC model[7], suggesting HDAC inhibition might be the approach to block the development of cisplatin resistance. Considering the P-gp-mediated drug resistance, whether HDAC inhibition could reverse the progression of cisplatin resistance in NSCLCs is still not elucidated

Methods

Results

Conclusion