CREB5: A Master Regulator of Stem Cell-Like Programs in Prostate Cancer Progression

·11 min·1 clip

How does a transcription factor called CREB-5 drive aggressive, therapy-resistant prostate cancer when standard treatments fail?

This episode presents research findings from a paper published in Oncotarget Volume 17 titled 'CREB-5 Regulates Stem Cell-Like Transcriptional Programs to Enhance Tumor Progression in Prostate Cancer.' The study addresses the challenge of prostate tumors that develop resistance to androgen receptor-targeted therapies by switching to AR-independent programs resembling basal or stem cell-like states. Researchers analyzed transcriptomic data from 493 primary prostate tumors from TCGA and 208 castration-resistant prostate cancers from the SU2C dataset. They found CREB-5 ranked among the top genes associated with basal, club, and hillock epithelial cell identities but was among the lowest associated with luminal identity. CREB-5 expression was inversely correlated with AR activity and positively correlated with KLF-5, another transcription factor linked to AR-independent resistance. Molecular analysis revealed CREB-5 showed highly concordant behavior with 25 transcription factors defining a stem cell-like subtype of CRPC. The relationship between CREB-5 and AP1 transcription factor FOSL1 was particularly strong, with an R-squared of 0.980 between their gene behaviors across all genes in the dataset. Functional validation experiments showed CREB-5 overexpression increased FOSL1 expression in prostate cancer cells under various conditions. Protein-protein interaction studies revealed CREB-5 interacts with several AP1 factors including JUN, JUNB, JUND, ATF2, and ATF7. CHIP-sequencing showed CREB-5 binds to transcriptional start sites of AP1 genes and stem cell-like genes. Phenotypic experiments demonstrated CREB-5 overexpression significantly increased tumor-sphere formation in hormone-sensitive prostate cancer cells. In vivo studies showed CREB-5 overexpression increased tumor volume in both castrated and non-castrated mice. The research suggests CREB-5 promotes tumor formation through stemness rather than simply accelerating proliferation. Clinical implications include CREB-5 as a potential biomarker for identifying patients at risk of developing therapy resistance. The interaction between CREB-5 and AP1 factors points to potential therapeutic strategies targeting these complexes. The study establishes CREB-5 as a key driver of basal and stem cell-like transcriptional programs in prostate cancer.

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