MicroRNA-644a disrupts oncogenic transformation and Warburg effect by directly downregulating multiple genes of tumor-promoting pathways

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 co-regulators and anti-apoptosis factors Bcl-xl and Bcl-2. 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, IGF-1R and GAPDH expression. RNA-seq analysis revealed an analogous downregulation of these factors in animal tumor xenografts. This data demonstrates miR-644a mediated fine-tuning of oncogenic stimulating pathways and resultant potentiation of the effects of Enzalutamide in CRPC animal models.

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