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| Status |
Public on Dec 02, 2019 |
| Title |
MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.
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| Overall design |
LNCaP-AI and DU-145 cells stably expressing a tet-MUCshRNA vector were treated with vehicle control or doxycycline. Total RNA from cells cultured in triplicates was isolated and used for library preparation.
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| Contributor(s) |
Kufe D RH, Mark L, Qiang H |
| Citation(s) |
31953400, 34163028, 35127252, 36754452 |
| |
| Submission date |
Oct 24, 2019 |
| Last update date |
Jun 02, 2023 |
| Contact name |
Qiang Hu |
| E-mail(s) |
Qiang.Hu@RoswellPark.org
|
| Organization name |
Roswell Park Cancer Institute
|
| Street address |
Elm & Carlton Streets
|
| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14263 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA579338 |
| SRA |
SRP226833 |
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