The WAVE3-YB1 interaction regulates cancer stem cells activity in breast cancer
Metrics: PDF 1606 views | HTML 3009 views | ?
Kamila Bledzka1, Barbara Schiemann2, William P. Schiemann2, Paul Fox3, Edward F. Plow1 and Khalid Sossey-Alaoui1
1Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
2Case Comprehensive Cancer Center, Cleveland, Ohio, USA
3Department of Cellular and Molecular Medicine, Cleveland, Ohio, USA
Khalid Sossey-Alaoui, email: [email protected]
Keywords: WAVE3, CSCs, YB1, TNBC, chemoresistance
Abbreviations: CSCs: Cancer stem cells; TNBC: Triple negative breast cancer; YB1: Y-box binding protein 1; ELDA: Extreme limited dilution assay
Received: July 22, 2017 Accepted: September 29, 2017 Published: October 24, 2017
Resistance to therapy is the main cause of tumor recurrence and metastasis and cancer stem cells (CSCs) play a crucial role in this process, especially in triple-negative breast cancers (TNBCs). Unfortunately, no FDA-approved treatment is currently available for this subtype of BC, which explains the high rate of mortality in patients with TNBC tumors. WAVE3, a member of the WASP/WAVE actin-cytoskeleton remodeling family of protein, has been established as a major driver of tumor progression and metastasis of several solid tumors, including those originating in the breast. Our recently published studies found WAVE3 to mediate the process of chemoresistance in TNBCs. The molecular mechanisms whereby WAVE3 regulates chemoresistance in TNBC tumors remains largely unknown, as does the role of WAVE3 in CSC maintenance. Here we show that WAVE3 promotes CSC self-renewal and regulates transcription of CSC-specific genes, which, in part, provides a mechanistic explanation for the function of WAVE3 in chemoresistance in TNBCs. Our data show that WAVE3 is enriched in the CSC-subpopulation of TNBC cell lines. Knockout of WAVE3 via CRISPR/Cas9 significantly attenuates the CSC-subpopulation and inhibits transcription of CSC transcription factors. Mechanistically, we established a link between WAVE3 and the Y-box-binding protein-1 (YB1), a transcription factor and CSC-maintenance gene. Indeed, the interaction of WAVE3 with YB1 is required for YB1 translocation to the nucleus of cancer cells, and activation of transcription of CSC-specific genes. Our findings identify a new WAVE3/YB1 signaling axis that regulates the CSC-mediated resistance to therapy and opens a new therapeutic window for TNBCs treatment.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.