HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Anqi Li,Wentao Yang,Zebing Liu,Shuling Zhou,Yaoxing Xiao,Yan Xu,Ming Li

doi:10.18632/oncotarget.9274

Anqi Li, Wentao Yang + Show 5 more

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https://doi.org/10.18632/oncotarget.9274

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Abstract

PurposeHistone deacetylase 5 (HDAC5) is an important protein in neural and cardiac diseases and a potential drug target. However, little is known regarding the specific role of HDAC5 in breast cancer (BC). We aimed to evaluate HDAC5 expression in human breast tumors and to determine the effects of the inhibition of HDAC5 expression in BC cells.Experimental designHDAC5 expression was evaluated in BC patients and was correlated with clinical features and with patient prognosis. Functional experiments were performed using shRNA and the selective HDAC inhibitor LMK-235 for HDAC5 knockdown and inhibition in BC cells. The synergistic effects of LMK-235 with the proteasome inhibitor bortezomib were also examined.ResultsHDAC5 was extensively expressed in human BC tissues, and high HDAC5 expression was associated with an inferior prognosis. Knockdown of HDAC5 inhibited cell proliferation, migration, invasion, and enhanced apoptosis. The HDAC5 inhibitor LMK-235 inhibited cell growth and induced apoptosis, while the inclusion of bortezomib synergistically enhanced the efficacy of LMK-235.ConclusionsOur findings indicate that HDAC5 is a promising prognostic marker and drug target for BC and that the combination of LMK-235 and bortezomib presents a novel therapeutic strategy for BC.

Highlights

Breast cancer (BC) is the most common cancer and the leading cause of cancer-related death in women
Histone deacetylase 5 (HDAC5) was extensively expressed in human breast cancer (BC) tissues, and high HDAC5 expression was associated with an inferior prognosis
Our findings indicate that HDAC5 is a promising prognostic marker and drug target for BC and that the combination of LMK-235 and bortezomib presents a novel therapeutic strategy for BC

Summary

Introduction

Breast cancer (BC) is the most common cancer and the leading cause of cancer-related death in women. Advances in novel adjuvant therapies have markedly decreased BC-related mortality [1]. The problems of drug resistance and distant metastasis remain unresolved and have resulted in inadequate patient survival. To address these issues, more effective and less toxic targeted therapies are urgently required to improve the cure rate. Recent studies have reported the aberrant overexpression of HDAC5 in hepatocellular carcinoma [5] and high-risk medulloblastoma [6], whereas HDAC5 downregulation has been reported in colon cancer [7] and is associated with poor prognosis in lung cancer patients [8]. Peixoto et al demonstrated that HDAC5 maintains pericentric heterochromatin structures in human cancer cells and represents a potential anticancer drug target [9]. Hsieh et al reported that pan-HDAC inhibitors (pan-HDACis) induce BC apoptosis via the upregulation of microRNA (miR)-125a-5p, which posttranscriptionally silences HDAC5 [10]

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