Crosstalk between ATF4 and MTA1/HDAC1 promotes osteosarcoma progression.

Abstract

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.

• Authors: Heng Zeng, Jin-Ming Zhang, Yu Du, Jiang Wang, Ye Ren, Mi Li, Hao Li, Zhuo Cai, Qian Chu, Caihong Yang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 6 Pg. 7329-42 (Feb 09 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26797758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF4 protein, human
• Mta1 protein, human
• RNA, Messenger
• Repressor Proteins
• Trans-Activators
• Activating Transcription Factor 4
• HDAC1 protein, human
• Histone Deacetylase 1
• Histone Deacetylases

Topics

• Activating Transcription Factor 4 (genetics, metabolism)
• Animals
• Apoptosis
• Blotting, Western
• Bone Neoplasms (genetics, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Chromatin Immunoprecipitation
• Disease Progression
• Follow-Up Studies
• Histone Deacetylase 1 (genetics, metabolism)
• Histone Deacetylases (genetics, metabolism)
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Lung Neoplasms (genetics, metabolism, secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Staging
• Osteosarcoma (genetics, metabolism, pathology)
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Repressor Proteins (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Trans-Activators
• Transcription, Genetic
• Tumor Cells, Cultured
• Ubiquitination
• Xenograft Model Antitumor Assays