Post-transcriptional Gene Regulation by MicroRNA-194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer

Rayzel C Fernandes; John Toubia; Scott Townley; Adrienne R Hanson; B Kate Dredge; Katherine A Pillman; Andrew G Bert; Jean M Winter; Richard Iggo; Rajdeep Das; Daisuke Obinata; MURAL investigators; Shahneen Sandhu; Gail P Risbridger; Renea A Taylor; Mitchell G Lawrence; Lisa M Butler; Amina Zoubeidi; Philip A Gregory; Wayne D Tilley; Theresa E Hickey; Gregory J Goodall; Luke A Selth

doi:10.1016/j.celrep.2020.108585

Post-transcriptional Gene Regulation by MicroRNA-194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer

Cell Rep. 2021 Jan 5;34(1):108585. doi: 10.1016/j.celrep.2020.108585.

Authors

Rayzel C Fernandes¹, John Toubia², Scott Townley¹, Adrienne R Hanson¹, B Kate Dredge³, Katherine A Pillman³, Andrew G Bert³, Jean M Winter¹, Richard Iggo⁴, Rajdeep Das⁵, Daisuke Obinata⁶; MURAL investigators⁷; Shahneen Sandhu⁸, Gail P Risbridger⁹, Renea A Taylor¹⁰, Mitchell G Lawrence⁷, Lisa M Butler¹¹, Amina Zoubeidi¹², Philip A Gregory¹³, Wayne D Tilley¹, Theresa E Hickey¹, Gregory J Goodall¹⁴, Luke A Selth¹⁵

Affiliations

¹ Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia.
² ACRF Cancer Genomics Facility, Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Frome Road, Adelaide, SA 5005, Australia.
³ Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Adelaide, SA 5005, Australia.
⁴ Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia; Institut Bergonié Unicancer, INSERM U1218, Bordeaux, France.
⁵ Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia; Transplant Immunology Laboratory, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁶ Department of Urology, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Anatomy and Developmental Biology, Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Monash University, Clayton, VIC 3168, Australia.
⁷ Department of Anatomy and Developmental Biology, Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Monash University, Clayton, VIC 3168, Australia; Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia.
⁸ Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3000, Australia.
⁹ Department of Anatomy and Developmental Biology, Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Monash University, Clayton, VIC 3168, Australia; Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3000, Australia.
¹⁰ Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia; Department of Physiology, Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Monash University, Clayton, VIC 3168, Australia.
¹¹ South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia.
¹² The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
¹³ Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Adelaide, SA 5005, Australia; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia.
¹⁴ Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Adelaide, SA 5005, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia.
¹⁵ Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia. Electronic address: [email protected].

PMID: 33406413
DOI: 10.1016/j.celrep.2020.108585

Abstract

Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.

Keywords: FOXA1; lineage plasticity; miR-194; microRNA; neuroendocrine prostate cancer; post-transcriptional gene regulation; prostate cancer; transdifferentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Animals
Carcinoma, Neuroendocrine / genetics
Carcinoma, Neuroendocrine / metabolism
Cell Culture Techniques / methods
Cell Line, Tumor
Cell Lineage
Cell Transdifferentiation*
Gene Expression Regulation, Neoplastic
Hepatocyte Nuclear Factor 3-alpha / metabolism*
Humans
MAP Kinase Signaling System
Male
Mice
MicroRNAs / genetics*
MicroRNAs / metabolism*
PC-3 Cells
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism*
Receptors, Androgen / metabolism*
Signal Transduction

Substances

FOXA1 protein, human
Hepatocyte Nuclear Factor 3-alpha
MIRN194 microRNA, human
MicroRNAs
Receptors, Androgen