2. Academic Validation
  3. Overexpression of MTA1 inhibits the metastatic ability of ZR-75-30 cells in vitro by promoting MTA2 degradation

Overexpression of MTA1 inhibits the metastatic ability of ZR-75-30 cells in vitro by promoting MTA2 degradation

  • Cell Commun Signal. 2019 Jan 14;17(1):4. doi: 10.1186/s12964-019-0318-6.
Long Zhang 1,  Qi Wang 1,  Yuzhen Zhou 1,  Qianwen Ouyang 2,  Weixing Dai 3 4,  Jianfeng Chen 1 5,  Peipei Ding 1,  Ling Li 5,  Xin Zhang 1,  Wei Zhang 1,  Xinyue Lv 1,  Luying Li 1,  Pingzhao Zhang 1 5,  Guoxiang Cai 3 4,  Weiguo Hu 6 7 8
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.
  • 2 Department of Breast Surgery, The Third Hospital of Nanchang, China Jiangxi Province Key Laboratory for Breast Diseases, 2 South Xiangshan Road, Nanchang, 330009, Jiangxi, China.
  • 3 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.
  • 4 Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong'an Road, Shanghai, 200032, China.
  • 5 Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.
  • 6 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China. weiguohu@fudan.edu.cn.
  • 7 Department of Immunology, Shanghai Medical College, Fudan University, 130 Dong'an Road, Shanghai, 200032, China. weiguohu@fudan.edu.cn.
  • 8 Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong'an Road, Shanghai, 200032, China. weiguohu@fudan.edu.cn.
PMID: 30642362 DOI: 10.1186/s12964-019-0318-6
Abstract

Background: As the first member of the metastasis-associated protein (MTA) family, MTA1 and another MTA family member, MTA2, have both been reported to promote breast Cancer progression and metastasis. However, the difference and relationship between MTA1 and MTA2 have not been fully elucidated.

Methods: Transwell assays were used to assess the roles of MTA1 and MTA2 in the metastasis of ZR-75-30 luminal B breast Cancer cells in vitro. Immunoblotting and qRT-PCR were used to evaluate the effect of MTA1 overexpression on MTA2. Proteases that cleave MTA2 were predicted using an online web server. The role of neutrophil Elastase (NE) in MTA1 overexpression-induced MTA2 downregulation was confirmed by specific inhibitor treatment, knockdown, overexpression and immunocytochemistry, and NE cleavage sites in MTA2 were confirmed by MTA2 truncation and mutation. The effect of MTA1 overexpression on the intrinsic inhibitor of NE, elafin, was detected by qRT-PCR, immunoblotting and treatment with inhibitors.

Results: MTA1 overexpression inhibited, while MTA2 promoted the metastasis of ZR-75-30 cells in vitro. MTA1 overexpression downregulated MTA2 expression at the protein level rather than the mRNA level. NE was predicted to cleave MTA2 and was responsible for MTA1 overexpression-induced MTA2 degradation. NE was found to cleave MTA2 in the C-terminus at the 486, 497, 542, 583 and 621 sites. MTA1 overexpression activated NE by downregulating elafin in a histone deacetylase- and DNA methyltransferase-dependent manner.

Conclusions: MTA1 and MTA2 play opposing roles in the metastasis of ZR-75-30 luminal B breast Cancer cells in vitro. MTA1 downregulates MTA2 at the protein level by epigenetically repressing the expression of elafin and releasing the inhibition of neutrophil Elastase, which cleaves MTA2 in the C-terminus at multiple specific sites.

Keywords

Breast cancer metastasis; Elafin; MTA1; MTA2; Neutrophil elastase.

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