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EVI1 promotes metastasis by downregulating TIMP2 in metastatic colon and breast cancer cells.
Suresh, Voddu; Singh, Vivek Kumar; Nayak, Kasturi Bala; Senapati, Shantibhusan; Chakraborty, Soumen.
Affiliation
  • Pradeepa; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India.
  • Suresh V; Tumor Microenvironment and Animal Models Group, Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India.
  • Singh VK; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India.
  • Nayak KB; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India.
  • Senapati S; Tumor Microenvironment and Animal Models Group, Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India.
  • Chakraborty S; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India. Electronic address: soumen_ils@yahoo.co.in.
Int J Biochem Cell Biol ; 142: 106118, 2022 01.
Article in En | MEDLINE | ID: mdl-34800694
ABSTRACT
Ecotropic viral integration site-1 (EVI1) is an oncogenic zinc finger transcription factor whose expression is frequently upregulated in a variety of cancers, including both myeloid malignancies and solid tumors. Previously, our group has shown that EVI1 knockdown minimizes the metastatic potential of colon cancer cells compared to that of control cells. In this study, to identify the potential targets that regulate cancer metastasis, control and EVI1 knockdown colon cancer cells were subjected to microarray. Differential gene expression analysis revealed significant downregulation of tissue inhibitor of matrix metalloproteinase-2 (TIMP2) in EVI1 expressing cells. EVI1 knockdown increased TIMP2 protein expression levels and reduced wound healing and migration capacity in metastatic cells. Mechanistically, the TIMP2 promoter harbors potential binding sites for EVI1; EVI1 binds to TIMP2 promoter and represses its expression, as observed using ChIP and luciferase assay, respectively. TIMP2 is an important metastasis suppressor gene; however, its function is suppressed in many cancers through hypermethylation. Thus, demethylation could prove to be a potential alternative to reactivate TIMP2 functional activity. Immunoprecipitation analysis showed that DNA-methyltransferase 1 (DNMT1), which plays a vital role in maintaining the genome methylation pattern during DNA replication and repair, interacts with EVI1 to promote TIMP2 silencing. Treating cancer cells in vitro with a known demethylation agent, 5-aza-2'-deoxycytidine (Aza-D), restored the optimal TIMP2 expression without altering EVI1 binding efficiency and reduced relative wound healing potential of cancer cells. Animal studies showed that Aza-D treated cells injected through the intravenous route exhibited reduced liver and skin metastasis when compared to non-treated cells. Furthermore, Aza-D treatment in mice delayed the metastasis progression compared to the vehicle treated group. Thus, the present study provides an insight into the therapeutic applications of demethylating agents to reduce cancer metastasis in models with EVI1 overexpressing tumors.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Down-Regulation Type of study: Prognostic_studies Language: En Journal: Int J Biochem Cell Biol Journal subject: BIOQUIMICA Year: 2022 Document type: Article Affiliation country: India

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Down-Regulation Type of study: Prognostic_studies Language: En Journal: Int J Biochem Cell Biol Journal subject: BIOQUIMICA Year: 2022 Document type: Article Affiliation country: India