MiR-644a disrupts oncogenic transformation and warburg effect by direct modulation of multiple genes of tumor-promoting pathways

Jey S. Ebron, Eswar Shankar, Jagjit Singh, Kavleen Sikand, Crystal M. Weyman, Sanjay Gupta, Daniel J. Lindner, Xiaoqi Liu, Moray J. Campbell, Girish C. Shukla

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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. Significance: This study demonstrates that miR-644a therapeutically influences the CRPC tumor microenvironment by suppressing androgen signaling and additional genes involved in metabolism, proliferation, Warburg effect, and EMT, to potentiate the enzalutamide therapy.

Original languageEnglish
Pages (from-to)1844-1856
Number of pages13
JournalCancer Research
Volume79
Issue number8
DOIs
StatePublished - Apr 15 2019

Bibliographical note

Publisher Copyright:
© 2019 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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