The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

Neha Singh, Varune R. Ramnarine, Jin H. Song, Ritu Pandey, Sathish K. R. Padi, Mannan Nouri, Virginie Olive, Maxim Kobelev, Koichi Okumura, David McCarthy, Michelle M. Hanna, Piali Mukherjee, Belinda Sun, Benjamin R. Lee, J. Brandon Parker, Debabrata Chakravarti, Noel A. Warfel, Muhan Zhou, Jeremiah J. Bearss, Ewan A. Gibb, Mohammed Alshalalfa, R. Jefferey Karnes, Eric J. Small, Rahul Aggarwal, Felix Feng, Yuzhuo Wang, Ralph Buttyan, Amina Zoubeidi, Mark Rubin, Martin Gleave, Frank J. Slack, Elai Davicioni, Himisha Beltran, Colin Collins () and Andrew S. Kraft ()
Additional contact information
Neha Singh: University of Arizona Cancer Center, University of Arizona
Varune R. Ramnarine: University of British Columbia
Jin H. Song: University of Arizona Cancer Center, University of Arizona
Ritu Pandey: University of Arizona Cancer Center, University of Arizona
Sathish K. R. Padi: University of Arizona Cancer Center, University of Arizona
Mannan Nouri: University of British Columbia
Virginie Olive: University of Arizona Cancer Center, University of Arizona
Maxim Kobelev: University of British Columbia
Koichi Okumura: University of Arizona Cancer Center, University of Arizona
David McCarthy: Inc., 8821N. 7th St. STE 300
Michelle M. Hanna: Inc., 8821N. 7th St. STE 300
Piali Mukherjee: Weill Cornell Medicine
Belinda Sun: University of Arizona
Benjamin R. Lee: University of Arizona Cancer Center, University of Arizona
J. Brandon Parker: Northwestern University
Debabrata Chakravarti: Northwestern University
Noel A. Warfel: University of Arizona Cancer Center, University of Arizona
Muhan Zhou: University of Arizona Cancer Center, University of Arizona
Jeremiah J. Bearss: University of Arizona Cancer Center, University of Arizona
Ewan A. Gibb: Decipher Biosciences, Inc
Mohammed Alshalalfa: University of California San Francisco
R. Jefferey Karnes: Mayo Clinic College of Medicine
Eric J. Small: University of California San Francisco
Rahul Aggarwal: University of California San Francisco
Felix Feng: University of California San Francisco
Yuzhuo Wang: University of British Columbia
Ralph Buttyan: University of British Columbia
Amina Zoubeidi: University of British Columbia
Mark Rubin: University of Bern
Martin Gleave: University of British Columbia
Frank J. Slack: Harvard Medical School
Elai Davicioni: Decipher Biosciences, Inc
Himisha Beltran: Dana-Farber Cancer Institute
Colin Collins: University of British Columbia
Andrew S. Kraft: University of Arizona Cancer Center, University of Arizona

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.

Date: 2021
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DOI: 10.1038/s41467-021-26901-9

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