KMT2C deficiency drives transdifferentiation of double-negative prostate cancer and confer resistance to AR-targeted...

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Double-negative prostate cancer (DNPC) is an aggressive subtype often developing after androgen deprivation therapy (ADT).
• The cellular origins and molecular drivers of DNPC remain poorly understood.
• Understanding DNPC development is crucial for improving treatment outcomes.

Purpose of the Study:

• To investigate the role of KMT2C in the development of DNPC following ADT.
• To elucidate the molecular mechanisms by which KMT2C loss promotes DNPC transdifferentiation.
• To identify potential therapeutic strategies targeting DNPC.

Main Methods:

• Analysis of tumor samples from patients undergoing ADT.
• CRISPR screening to identify genes regulating DNPC transition.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to assess KMT2C binding.
• RNA sequencing and Western blotting to evaluate gene and protein expression.
• Cellular assays to study transdifferentiation and signaling pathways.

Main Results:

• Tumors with KMT2C mutation or loss showed increased susceptibility to DNPC development post-ADT.
• DNPC primarily originates from luminal cell transdifferentiation, not basal cell transformation.
• KMT2C loss disrupts enhancer-promoter communication, reduces ASPP2 expression, and triggers ΔNp63-dependent transdifferentiation.
• DNPC growth is fueled by fatty acid synthesis via ΔNp63-mediated SREBP1c activation and HRAS palmitoylation.

Conclusions:

• KMT2C acts as an epigenetic checkpoint preventing DNPC development.
• Loss of KMT2C facilitates prostate adenocarcinoma to DNPC transition.
• Targeting fatty acid synthesis presents a promising therapeutic avenue for DNPC.