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RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition

Oncogene volume 41, pages 852–864 (2022)Cite this article

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Abstract

Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1 loss is also a critical event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa) induced by the androgen receptor (AR) signaling inhibition (ARSi). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of Rb inactivation on PCa progression and linage plasticity has been previously studied, there is a pressing need to fully understand underlying mechanisms and identify vulnerabilities that can be therapeutically targeted in Rb-deficient CRPC. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb-directly regulated genes and revealed that Rb has distinct binding sites and targets in CRPC with different genomic backgrounds. Significantly, we show that E2F1 chromatin binding and transcription activity in Rb-deficient CRPC are highly dependent on LSD1/KDM1A, and that Rb inactivation sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights into Rb activity in PCa progression and suggest that targeting LSD1 activity with small molecule inhibitors may be a potential treatment strategy to treat Rb-deficient CRPC.

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Fig. 1: Identification of Rb-directly regulated genes in C4-2 CRPC cells.
Fig. 2: Rb directly represses distinct gene subsets in VCaP cells.
Fig. 3: Increased expression of Rb-directly repressed genes is associated with the aggressiveness of CRPC.
Fig. 4: Rb-directly repressed genes are upregulated in CRPC-NE.
Fig. 5: RB1 loss increases the expression of LSD1-activated genes.
Fig. 6: RB1 loss sensitizes CRPC to LSD1 inhibition.

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Acknowledgements

This work is supported by grants from NIH (R00 CA166507 and R01 CA211350 to CC, U54 CA156734 to JAM), DOD (W81XWH-16-1-0445, W81XWH-19-1-0361, and W81XWH-21-1-0267 to CC, W81XWH-19-1-0777 to SG), CIHR (142246, 152863, 152864, and 159567 to HHH), and Terry Fox Frontiers Program Project Grants (1090 P3 to HHH). MLiu was supported by the graduate fellowship from the Integrative Biosciences Program at the University of Massachusetts Boston. WH and ZW were supported by CSM (College of Science and Mathematics) Dean’s Doctoral Research Fellowship from the University of Massachusetts Boston. HHH holds Joey and Toby Tanenbaum Brazilian Ball Chair in Prostate Cancer.

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  1. These authors contributed equally: Wanting Han, Mingyu Liu.

Authors and Affiliations

  1. Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA

    Wanting Han, Mingyu Liu, Dong Han, Muqing Li, Anthia A. Toure, Zifeng Wang, Anna Besschetnova, Susan Patalano, Jill A. Macoska, Shuai Gao & Changmeng Cai

  2. Department of Biology, University of Massachusetts Boston, Boston, MA, 02125, USA

    Wanting Han, Mingyu Liu, Muqing Li, Anthia A. Toure, Zifeng Wang, Anna Besschetnova, Susan Patalano, Jill A. Macoska, Shuai Gao & Changmeng Cai

  3. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Housheng Hansen He

  4. Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G1L7, Canada

    Housheng Hansen He

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Contributions

CC, SG, WH, and MLiu designed the study. WH, MLiu, DH, MLi, A.AT, ZW, A.B, and SG performed experiments and analyzed the results. WH, MLiu, DH, SP, and JAM performed deep sequencing analyses. CC, WH, MLiu, HHH, and SG wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Changmeng Cai.

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Han, W., Liu, M., Han, D. et al. RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition. Oncogene 41, 852–864 (2022). https://doi.org/10.1038/s41388-021-02135-3

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