A MicroRNA/Ubiquitin Ligase Feedback Loop Regulates Slug-Mediated Invasion in Breast Cancer

• Published in: Neoplasia (New York, N.Y.) Vol. 19; no. 6; pp. 483 - 495
• Main Authors: Manne, Rajesh Kumar, Agrawal, Yashika, Bargale, Anil, Patel, Asha, Paul, Debasish, Gupta, Neha Anilkumar, Rapole, Srikanth, Seshadri, Vasudevan, Subramanyam, Deepa, Shetty, Praveenkumar, Santra, Manas Kumar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2017; Elsevier Limited; Neoplasia Press; Elsevier
• Subjects: Breast cancer; Cancer; Feedback; Genetic transformation; Genotoxicity; Invasiveness; Mesenchyme; MicroRNAs; miRNA; Oncology; Original article; Phenotypes; Post-transcription; Proteasomes; Tumor suppressor genes; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1016/j.neo.2017.02.013

Abstract The transformation of a normal cell to cancer requires the derail of multiple pathways. Normal signaling in a cell is regulated at multiple stages by the presence of feedback loops, calibration of levels of proteins by their regulated turnover, and posttranscriptional regulation, to name a few. The tumor suppressor protein FBXO31 is a component of the SCF E3 ubiquitin ligase and is required to arrest cells at G1 following genotoxic stresses. Due to its growth-suppression activity, it is underexpressed in many cancers. However, the molecular mechanism underlying the translational regulation of FBXO31 remains unclear. Here we show that the oncogenic microRNAs miR-93 and miR-106a repress FBXO31, resulting in the upregulation of Slug, which is involved in epithelial-mesenchymal transition and cell invasion. FBXO31 targets and ubiquitylates Slug for proteasomal degradation. However, this mechanism is repressed in breast tumors where miR-93 and miR-106a are overexpressed. Our study further unravels an interesting mechanism whereby Slug drives the expression of miR-93 and miR-106a, thus establishing a positive feedback loop to maintain an invasive phenotype. Together, these results establish the presence of interplay between microRNAs and the ubiquitination machinery, which together regulate cancer cell invasion.