TY - JOUR
T1 - TBX2 drives neuroendocrine prostate cancer through exosome-mediated repression of miR-200c-3p
AU - Patel, Girijesh Kumar
AU - Dutta, Sayanika
AU - Syed, Mosharaf Mahmud
AU - Ramachandran, Sabarish
AU - Sharma, Monica
AU - Rajamanickam, Venkatesh
AU - Ganapathy, Vadivel
AU - Degraff, David J.
AU - Pruitt, Kevin
AU - Tripathi, Manisha
AU - Nandana, Srinivas
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
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U2 - 10.3390/cancers13195020
DO - 10.3390/cancers13195020
M3 - Article
C2 - 34638504
AN - SCOPUS:85116416706
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 19
M1 - 5020
ER -