School of Medicine and Health Sciences Poster Presentations

Title

Regulation of Oncogenic Phenotype by a miR-200c/141-BMI1 Autoregulatory Loop

Poster Number

134

Document Type

Poster

Publication Date

3-2016

Abstract

The polycomb group protein BMI1 is an important regulator of breast cancer stem cell (BCSC) phenotype and is often overexpressed in breast cancer cells. Its overexpression leads to increase in BCSC fraction and therapy resistance. BMI1 functions via polycomb repressive complex 1 (PRC1) -mediated gene silencing and also via PRC1-independent transcriptional activities. BMI1 itself is posttranscriptionally regulated by several microRNAs including miR-200 family members. Here we studied cross-regulation of the miR-200c/141 cluster by BMI1 and its relevance to oncogenic function of BMI1. We show that BMI1 functions as a transcriptional repressor of the miR-200c/141 cluster and that BMI1 inhibitors upregulate expression of miR-200c and miR-141. Our results suggest that BMI1 directly binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box2 and Z-box1 to repress expression of the miR-200c/141 cluster. We also show that PTC-209, a small molecule inhibitor of BMI1 strongly induces cellular senescence and transcriptionally upregulates expression of miR-200c/141 cluster in breast cancer cells. Furthermore, inhibition of expression of miR-200c or miR-141 overcomes tumor suppressive effects of PTC-209 on oncogenic phenotype such as inhibition of migration and invasion and downregulation of BCSC phenotype.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Open Access

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Presented at: GW Research Days 2016

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Regulation of Oncogenic Phenotype by a miR-200c/141-BMI1 Autoregulatory Loop

The polycomb group protein BMI1 is an important regulator of breast cancer stem cell (BCSC) phenotype and is often overexpressed in breast cancer cells. Its overexpression leads to increase in BCSC fraction and therapy resistance. BMI1 functions via polycomb repressive complex 1 (PRC1) -mediated gene silencing and also via PRC1-independent transcriptional activities. BMI1 itself is posttranscriptionally regulated by several microRNAs including miR-200 family members. Here we studied cross-regulation of the miR-200c/141 cluster by BMI1 and its relevance to oncogenic function of BMI1. We show that BMI1 functions as a transcriptional repressor of the miR-200c/141 cluster and that BMI1 inhibitors upregulate expression of miR-200c and miR-141. Our results suggest that BMI1 directly binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box2 and Z-box1 to repress expression of the miR-200c/141 cluster. We also show that PTC-209, a small molecule inhibitor of BMI1 strongly induces cellular senescence and transcriptionally upregulates expression of miR-200c/141 cluster in breast cancer cells. Furthermore, inhibition of expression of miR-200c or miR-141 overcomes tumor suppressive effects of PTC-209 on oncogenic phenotype such as inhibition of migration and invasion and downregulation of BCSC phenotype.