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

20 Scopus citations


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
Issue number8
StatePublished - Apr 15 2019

Bibliographical note

Funding Information:
We are thankful to Drs. John Kirwan and Anny Mulya, Department of Pathology, Lerner Research Institute, Cleveland Clinic, for help with Seahorse flux analyzer. Research in G.C. Shukla lab is supported by the grants W81XWH-14-1-0508 and W81XWH-14-1-0509 from the Department of the Defense Prostate Cancer Research Program. We acknowledge the use of resources and services provided by the PCBN funded by the grants PCBN W81XWH-10-2-0056 and W81XWH-10-2-0046. G.C. Shukla lab also acknowledges the support of CSU Faculty Research Development funding and John Vitullo Bridge funding provided by the Center for Gene Regulation in Health and Disease. S. Gupta lab is supported by the Department of Defense W81XWH-15-1-0558, USPHS R21CA193080, R03CA186179, and VA Merit Review 1I01BX002494 grants. X. Liu acknowledges support from an R01 CA157429 grant from NIH.

Publisher Copyright:
© 2019 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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