HDAC10 promotes lung cancer proliferation via AKT phosphorylation.

Yiwei Yang,Wen Chen,Hsin-Tzu Wang,Songcheng Zhu,Chenxin Wang,Yitong Huang,Zhantong Wang,Dan Ye,Jiuhong Kang,Baoyu Duan,Jiajie Xi,Ye Leng,Ruiqi Jing,Wenwen Jia,Guiying Wang

doi:10.18632/oncotarget.10673

Yiwei Yang, Wen Chen + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.10673

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Journal: Oncotarget	Publication Date: Jul 18, 2016
Citations: 53	License type: cc-by

Affiliation: Shanghai First Maternity and Infant Hospital

Abstract

Histone deacetylase 10 (HDAC10) is a member of the class II HDACs, and its role in cancer is emerging. In this study, we found that HDAC10 is highly expressed in lung cancer tissues. It resides mainly in the cytoplasm of lung cancer cells but resides in the nucleus of adjacent normal cells. Further examinations revealed that HDAC10 resides in the cytoplasm in multiple lung cancer cell lines, including the A549, H358 and H460 cell lines, but mainly resides in the nucleus of normal lung epithelial 16HBE cells. A leucine-rich motif, R505L506L507C508V509A510L511, was identified as its nuclear localization signal (NLS), and a mutant (Mut-505-511) featuring mutations to A at each of its original R and L positions was found to be nuclear-localization defective. Functional analysis revealed that HDAC10 promoted lung cancer cell growth and that its knockdown induced cell cycle arrest and apoptosis. Mechanistic studies showed that HDAC10 knockdown significantly decreased the phosphorylation of AKT at Ser473 and that AKT expression significantly rescued the cell cycle arrest and apoptosis elicited by HDAC10 knockdown. A co-immunoprecipitation assay suggested that HDAC10 interacts with AKT and that inhibition of HDAC10 activity decreases its interaction with and phosphorylation of AKT. Finally, we confirmed that HDAC10 promoted lung cancer proliferation in a mouse model. Our study demonstrated that HDAC10 localizes and functions in the cytoplasm of lung cancer cells, thereby underscoring its potential role in the diagnosis and treatment of lung cancer.

Highlights

Lung cancer, 80-85% of which comprises nonsmall cell lung cancer (NSCLC), is the fastest growing malignant cancer worldwide [1,2,3,4]
We found that the cytoplasmic signal of Histone deacetylase 10 (HDAC10) in cancer tissue was higher than in normal tissue (Figure 1C) and that the difference between the signals was statistically significant (Figure 1D)
Current chemotherapy regimens for advanced NSCLC elicit only modest increases in survival time, largely because symptoms occur only when the disease has reached an advanced stage, and drug resistance is inherent in tumour cells before therapy is initiated [5, 28]

Summary

Introduction

80-85% of which comprises nonsmall cell lung cancer (NSCLC), is the fastest growing malignant cancer worldwide [1,2,3,4]. The molecular mechanism underlying lung cancer development is associated with alterations in signal transduction that result from aberrant expression of oncogenes or tumour suppressor genes [5]. Histone deacetylase (HDAC)mediated silencing of tumour suppressor genes, such as AKT, GSK3β, c-MYC and p53, has been implicated in cancer development [6,7,8,9,10,11]. An HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), induced significant growth arrest in NSCLC cells, which may represent a novel approach to the treatment of NSCLC [12, 13]. Studies of the function and molecular mechanisms underlying the involvement of HDACs in lung cancer have provided a clinical basis for targeting HDACs in lung cancer treatment [13]

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