MiR-644a Disrupts Oncogenic Transformation and Warburg Effect by Direct Modulation of Multiple Genes of Tumor-Promoting Pathways
Abstract
Castration-resistant prostate cancer (CRPC) is defined by tumor microenvironment heterogeneity affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), and aberrant activation of transcription factors including androgen receptor (AR) and c-Myc. Using in vitro, in vivo, and animal models, we find a direct correlation between miR-644a downregulation and dysregulation of essential cellular processes. MiR-644a downregulated expression of diverse tumor microenvironment drivers including c-Myc, AR coregulators, and antiapoptosis factors Bcl-xl and Bcl2. Moreover, miR-644a modulates epithelial–mesenchymal transition (EMT) by directly targeting EMT-promoting factors ZEB1, cdk6, and Snail. Finally, miR-644a expression suppresses the Warburg effect by direct targeting of c-Myc, Akt, IGF1R, and GAPDH expression. RNA sequencing analysis revealed an analogous downregulation of these factors in animal tumor xenografts. These data demonstrate miR-644a mediated fine-tuning of oncogenesis, stimulating pathways and resultant potentiation of enzalutamide therapy in CRPC patients.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 15, 2019
- Source ID
- 10.1158/0008-5472.can-18-2993
Entities
People
- Crystal M. Weyman
- Daniel J. Lindner
- Eswar Shankar
- Girish C. Shukla
- Jagjit Singh
- Jey S. Ebron
- Kavleen Sikand
- Moray J Campbell
- Sanjay Gupta
- Xiaoqi Liu
Organizations
- Case Western Reserve University
- Cleveland Clinic
- Cleveland State University
- National Institutes of Health
- Ohio State University
- Panjab University
- United States Department of Defense
- United States Department of Veterans Affairs
- United States Public Health Service
- University of Kentucky