Epigenetic Derepression of PROX1 Promotes Neuroendocrine Prostate Cancer Progression

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Prostate cancer (PC) can transform into aggressive neuroendocrine prostate cancer (NEPC).
• This transformation involves epigenetic changes, including Polycomb complex 2 (PRC2) activity, and altered expression of transcription factors like prospero-homeobox 1 (PROX1).

Purpose of the Study:

• To functionally characterize the role of PROX1 in NEPC.
• To investigate PROX1 as a potential therapeutic target in NEPC.

Main Methods:

• CRISPR screening in NEPC patient-derived organoid models.
• PROX1 knockout and overexpression experiments in prostate cancer models.
• Transcriptomic and cistromic analyses.
• Immunoprecipitation followed by mass spectrometry.
• Inhibition of predicted upstream kinases (CHEK1, CDK2).

Main Results:

• PROX1 is essential for NEPC cell growth, with high cellular dependency observed.
• PROX1 knockout inhibited NEPC tumor growth; PROX1 overexpression promoted adenocarcinoma growth and metastasis.
• PROX1 regulates NEPC-specific transcriptional programs.
• Phosphorylation sites in PROX1's DNA-binding domain are critical for its function.
• CHEK1 and CDK2 phosphorylate PROX1, and their inhibition reduces NEPC viability.

Conclusions:

• PROX1 plays a critical role in the development and progression of NEPC.
• PROX1 phosphorylation in its DNA-binding domain is a key mechanism for its function.
• Targeting PROX1 phosphorylation via CHEK1 or CDK2 inhibition presents a potential therapeutic strategy for NEPC.