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DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via
Roosa Kaarijärvi1, Heidi Kaljunen1, Lucia Nappi2
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Abstract:
Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a neuron-like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine-related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 decreases proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype, and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a driver of t-NEPC progression.
Insights
Androgen receptor (AR) inhibition in prostate cancer promotes neuroendocrine transformation by upregulating dihydropyrimidinase-related protein 5 (DPYSL5). This protein drives cancer cell plasticity and progression in treatment-induced neuroendocrine prostate cancer (t-NEPC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC).
- t-NEPC arises under androgen deprivation therapy (ADT), developing resistance to androgen receptor (AR) inhibitors.
- The underlying mechanisms of neuroendocrine transformation in prostate cancer remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms driving neuroendocrine differentiation in prostate cancer.
- To identify key proteins involved in the transition from CRPC to t-NEPC.
- To investigate the role of dihydropyrimidinase-related protein 5 (DPYSL5) in prostate cancer progression and neuroendocrine transformation.
Main Methods:
- Analysis of a unique cohort of 135 patient tumor samples, including 55 t-NEPC samples.
- Correlation analysis of DPYSL5 expression with neuroendocrine markers, AR, and PSA levels.
- Functional studies involving DPYSL5 overexpression and depletion in prostate cancer cell lines.
- Investigation of downstream signaling pathways, including EZH2 and PRC2 activation.
Main Results:
- High DPYSL5 expression was observed in t-NEPC patient tumors, correlating with neuroendocrine markers and inversely with AR and PSA.
- DPYSL5 overexpression induced a neuron-like phenotype, enhanced invasion and proliferation, and upregulated stemness and neuroendocrine markers.
- Mechanistically, DPYSL5 promoted prostate cancer cell plasticity via EZH2-mediated PRC2 activation.
- DPYSL5 depletion reduced proliferation, induced cell cycle arrest, reversed neuroendocrine phenotype, and upregulated luminal genes.
Conclusions:
- DPYSL5 plays a critical role in regulating prostate cancer cell plasticity and driving neuroendocrine transformation.
- The AR/DPYSL5/EZH2/PRC2 axis is identified as a key driver of treatment-induced neuroendocrine prostate cancer progression.
- Targeting DPYSL5 may offer a therapeutic strategy for managing t-NEPC.
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