Abstract
Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / genetics
-
Adenocarcinoma / pathology
-
Cell Line, Tumor
-
Cell Lineage*
-
Cell Plasticity*
-
Chromosomal Proteins, Non-Histone / metabolism*
-
Cohort Studies
-
DNA Helicases / genetics
-
DNA Helicases / metabolism
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Kaplan-Meier Estimate
-
Male
-
Models, Biological
-
Neoplasm Invasiveness
-
Neoplasm Proteins / metabolism
-
Neuroendocrine Tumors / metabolism
-
Neuroendocrine Tumors / pathology
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Prostatic Neoplasms / genetics
-
Prostatic Neoplasms / metabolism*
-
Prostatic Neoplasms / pathology*
-
Protein Subunits / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transcriptome / genetics
Substances
-
Chromosomal Proteins, Non-Histone
-
Neoplasm Proteins
-
Nuclear Proteins
-
Protein Subunits
-
SWI-SNF-B chromatin-remodeling complex
-
Transcription Factors
-
SMARCA4 protein, human
-
DNA Helicases