Aberrant expression of a gastrointestinal (GI)-lineage transcriptome, independent of androgen receptor (AR) signalling, can drive castration resistance in prostate cancer.

HNF4G binds to and maintains a cistrome that regulates a GI-lineage transcriptome

Investigators observed unexpected expression of a GI-lineage transcriptome in ∼30% of castration-resistant prostate cancer (CRPC) samples. “This transcriptome is governed by aberrant activation of GI transcriptional master regulators HNF1A and HNF4G,” Yu Chen, corresponding author, tells Nature Reviews Urology. “CRPC models that express this transcriptome require HNF1A and HNF4G for growth,” he continues. In vitro, knockdown of HNF1A and HNF4G in 22Rv1 cells (which express the GI-lineage transcriptome) suppressed cell growth. Furthermore, knockdown of HNF1A and HNF4G in patient-derived metastatic CRPC organoids that express these factors at high levels also suppressed growth. In vivo, 22Rv1-derived xenografts subjected to HNF4G suppression also showed inhibited growth.

Credit: P. Morgan/Macmillan Publishers Limited

Further analysis revealed that HNF4G binds to and maintains a cistrome that regulates a GI-lineage transcriptome in prostate cancer that is distinct from AR signalling. Moreover, in vitro, exogenous expression of HNF4G in hormone-sensitive LNCaP cells caused endogenous HNF1A expression and vice versa, and both treatments resulted in upregulation of genes associated with the GI-lineage transciptome. Interestingly, treatment of LNCaP xenografts (either expressing or not expressing HNF4G), with enzalutamide caused increased HNF4G expression.

“Enforced expression of HNF1A and HNF4G in hormone-sensitive models activates the GI transcriptome and conveys castration resistance,” Chen explains. “Going forward, we are working to define the role of HNF4G as a potential biomarker for resistance to AR-targeted therapies and to identify compounds that target HNF1A and HNF4G,” he concludes.