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Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182.

Publication ,  Journal Article
Sachdeva, M; Dodd, RD; Huang, Z; Grenier, C; Ma, Y; Lev, DC; Cardona, DM; Murphy, SK; Kirsch, DG
Published in: Cancer Lett
December 1, 2015

Accumulating evidence indicates that microRNAs (miRs) regulate cancer metastasis. We have shown that miR-182 drives sarcoma metastasis in vivo by coordinated regulation of multiple genes. Recently, we also demonstrated that in a subset of primary sarcomas that metastasize to the lung, miR-182 expression is elevated through binding of MyoD1 to the miR-182 promoter. However, it is not known if there are also transcription factors that inhibit miR-182 expression. Defining negative regulators of miR-182 expression may help explain why some sarcomas do not metastasize and may also identify pathways that can modulate miR-182 for therapeutic benefit. Here, we use an in silico screen, chromatin-immunoprecipitation, and luciferase reporter assays to discover that Kruppel like factor-3 (Klf-3) is a novel transcriptional repressor of miR-182. Knockdown of Klf-3 increases miR-182 expression, and stable overexpression of Klf-3, but not a DNA-binding mutant Klf-3, decreases miR-182 levels. Klf-3 expression is downregulated in both primary mouse and human metastatic sarcomas, and Klf-3 levels negatively correlate with miR-182 expression. Interestingly, Klf-3 also negatively regulates MyoD1, suggesting an alternative mechanism for Klf-3 to repress miR-182 expression in addition to direct binding of the miR-182 promoter. Using Methylation Specific PCR (MSP) and pyrosequencing assays, we found that Klf-3 is epigenetically silenced by DNA hypermethylation both in mouse and human sarcoma cells. Finally, we show the DNA methylation inhibitor 5'Azacytidine (Aza) restores Klf-3 expression while reducing miR-182 levels. Thus, our findings suggest that demethylating agents could potentially be used to modulate miR-182 levels as a therapeutic strategy.

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Published In

Cancer Lett

DOI

EISSN

1872-7980

Publication Date

December 1, 2015

Volume

369

Issue

1

Start / End Page

202 / 211

Location

Ireland

Related Subject Headings

  • Sarcoma
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • MicroRNAs
  • Mice, Transgenic
  • Mice, Nude
  • Lung Neoplasms
  • Kruppel-Like Transcription Factors
  • Humans
 

Citation

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Sachdeva, M., Dodd, R. D., Huang, Z., Grenier, C., Ma, Y., Lev, D. C., … Kirsch, D. G. (2015). Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182. Cancer Lett, 369(1), 202–211. https://doi.org/10.1016/j.canlet.2015.08.016
Sachdeva, Mohit, Rebecca D. Dodd, Zhiqing Huang, Carole Grenier, Yan Ma, Dina C. Lev, Diana M. Cardona, Susan K. Murphy, and David G. Kirsch. “Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182.Cancer Lett 369, no. 1 (December 1, 2015): 202–11. https://doi.org/10.1016/j.canlet.2015.08.016.
Sachdeva M, Dodd RD, Huang Z, Grenier C, Ma Y, Lev DC, et al. Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182. Cancer Lett. 2015 Dec 1;369(1):202–11.
Sachdeva, Mohit, et al. “Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182.Cancer Lett, vol. 369, no. 1, Dec. 2015, pp. 202–11. Pubmed, doi:10.1016/j.canlet.2015.08.016.
Sachdeva M, Dodd RD, Huang Z, Grenier C, Ma Y, Lev DC, Cardona DM, Murphy SK, Kirsch DG. Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182. Cancer Lett. 2015 Dec 1;369(1):202–211.
Journal cover image

Published In

Cancer Lett

DOI

EISSN

1872-7980

Publication Date

December 1, 2015

Volume

369

Issue

1

Start / End Page

202 / 211

Location

Ireland

Related Subject Headings

  • Sarcoma
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • MicroRNAs
  • Mice, Transgenic
  • Mice, Nude
  • Lung Neoplasms
  • Kruppel-Like Transcription Factors
  • Humans