Presentation Title

The Tumor Suppressor Runx1 is a Negative Regulator of Hypoxia-Inducible Factor-1α (HIF-1α) in Breast Cancer Cells

Abstract

The tumor response to oxygen deficiency (hypoxia) is associated with cancer cell survival, metastasis and resistance to chemotherapy. Hypoxia induces the stabilization of Hypoxia-Inducible Factor-1α (HIF-1α) which mediates the expression of genes that promote survival and angiogenesis. Runx1 is a transcription factor that is downregulated in aggressive breast cancer cells. In a preliminary RNA-Seq screen, the depletion of Runx1 resulted in upregulation of hypoxia-regulated genes. To explore this mechanism, we tested the hypothesis that Runx1 is a negative regulator of HIF-1α. To determine if the loss of Runx1 activity leads to an increase in HIF-1α protein level, MCF10A breast cancer cells were exposed to a Runx1 inhibitor, and levels of HIF-1α protein were measured by Western blot. Results showed that Runx1 inhibition significantly increased the level of HIF-1α, even in the absence of a proteasome inhibitor (p<0.05, n=5). In preliminary experiments, inhibition of Runx1 did not affect HIF-1α mRNA level, measured by qPCR. Future experiments will confirm the effects of Runx1 inhibition on HIF-α and will also measure other hypoxia-related genes. Additionally, overexpression of Runx1 is predicted to prevent the hypoxia-induction of HIF-1α. A better understanding of the regulation of hypoxia responses has important implications for developing effective cancer therapies.

Primary Faculty Mentor Name

Karen M. Lounsbury

Secondary Mentor NetID

Ajfritz, Gsstein

Secondary Mentor Name

Andrew J. Fritz, Gary S. Stein

Status

Undergraduate

Student College

College of Arts and Sciences

Program/Major

Biological Science

Primary Research Category

Biological Sciences

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The Tumor Suppressor Runx1 is a Negative Regulator of Hypoxia-Inducible Factor-1α (HIF-1α) in Breast Cancer Cells

The tumor response to oxygen deficiency (hypoxia) is associated with cancer cell survival, metastasis and resistance to chemotherapy. Hypoxia induces the stabilization of Hypoxia-Inducible Factor-1α (HIF-1α) which mediates the expression of genes that promote survival and angiogenesis. Runx1 is a transcription factor that is downregulated in aggressive breast cancer cells. In a preliminary RNA-Seq screen, the depletion of Runx1 resulted in upregulation of hypoxia-regulated genes. To explore this mechanism, we tested the hypothesis that Runx1 is a negative regulator of HIF-1α. To determine if the loss of Runx1 activity leads to an increase in HIF-1α protein level, MCF10A breast cancer cells were exposed to a Runx1 inhibitor, and levels of HIF-1α protein were measured by Western blot. Results showed that Runx1 inhibition significantly increased the level of HIF-1α, even in the absence of a proteasome inhibitor (p<0.05, n=5). In preliminary experiments, inhibition of Runx1 did not affect HIF-1α mRNA level, measured by qPCR. Future experiments will confirm the effects of Runx1 inhibition on HIF-α and will also measure other hypoxia-related genes. Additionally, overexpression of Runx1 is predicted to prevent the hypoxia-induction of HIF-1α. A better understanding of the regulation of hypoxia responses has important implications for developing effective cancer therapies.