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

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.

• Authors: Yuhong Sun, Xuefei Bao, Yong Ren, Lina Jia, Shenglan Zou, Jian Han, Mengyue Zhao, Mei Han, Hong Li, Qixiang Hua, Yi Fang, Jingyu Yang, Chunfu Wu, Guoliang Chen, Lihui Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 6 Pg. 400 (05 24 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31127087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Histone Deacetylase Inhibitors
• Proteins
• RNA, Small Interfering
• ornithine decarboxylase antizyme
• Histone Deacetylases
• Cisplatin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Animals
• Binding Sites
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Histone Deacetylase Inhibitors (chemical synthesis, pharmacology, therapeutic use)
• Histone Deacetylases (chemistry, metabolism)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Molecular Docking Simulation
• Promoter Regions, Genetic
• Proteins (antagonists & inhibitors, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Up-Regulation (drug effects)