TBX2 drives neuroendocrine prostate cancer through exosome-mediated repression of miR-200c-3p

Girijesh Kumar Patel, Sayanika Dutta, Mosharaf Mahmud Syed, Sabarish Ramachandran, Monica Sharma, Venkatesh Rajamanickam, Vadivel Ganapathy, David J. Degraff, Kevin Pruitt, Manisha Tripathi, Srinivas Nandana

Research output: Contribution to journalArticlepeer-review

Abstract

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c- 3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir- 200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effec-tor in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intra-cellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of prop-agation of the NEPC phenotype.

Original languageEnglish (US)
Article number5020
JournalCancers
Volume13
Issue number19
DOIs
StatePublished - Oct 1 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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