Research Papers:

Crosstalk between ATF4 and MTA1/HDAC1 promotes osteosarcoma progression

Heng Zeng _, Jin-ming Zhang, Yu Du, Jiang Wang, Ye Ren, Mi Li, Hao Li, Zhuo Cai, Qian Chu and Caihong Yang

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Oncotarget. 2016; 7:7329-7342. https://doi.org/10.18632/oncotarget.6940

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Heng Zeng1,*, Jin-ming Zhang1,*, Yu Du1,2,*, Jiang Wang1, Ye Ren1, Mi Li1, Hao Li1, Zhuo Cai1, Qian Chu3, Caihong Yang1

1Department of Orthopedics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China

2Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China

3Department of Oncology, Tongji Hospital of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Caihong Yang, e-mail: [email protected]

Keywords: activating transcription factor 4, metastasis-associated protein 1, osteosarcoma, histone deacetylase 1

Received: July 31, 2015      Accepted: January 01, 2016      Published: January 18, 2016


The stress response gene activating transcription factor 4 (ATF4) is involved in metastatic behavior and cellular protection. Here we show that ATF4 is upregulated in osteosarcoma (OS) cell lines and patient clinical samples as compared to matched non-tumor tissue. Overexpression of ATF4 in OS cells promoted cell proliferation, migration and lung metastasis. Furthermore, the expression of ATF4 was markedly reduced in metastasis associated protein (MTA1) or histone deacetylase 1 (HDAC1) knockdown OS cells, but MTA1 overexpression increased the stability and activity of ATF4 protein via ATF4 deacetylation by HDAC1. ATF4 in turn enhanced the expression of MTA1 and HDAC1 at the transcription level, suggesting a positive feedback loop between ATF4 and MTA1/HDAC1. Clinically, the level of ATF4 was positively correlated with that of MTA1 in OS. Mice injected with ATF4-overexpressing cells exhibited a higher rate of tumor growth, and the average weight of these tumors was ~90% greater than the controls. Taken together, these data establish a direct correlation between ATF4-induced OS progression and MTA1/HDAC1-associated metastasis, and support the potential therapeutic value of targeting ATF4 in the treatment of OS.

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