A groundbreaking study published on March 17, 2026, in the esteemed journal Oncotarget unveils the pivotal role of the transcription factor CREB5 in regulating stem cell-like transcriptional programs that drive tumor progression in prostate cancer. This landmark research, led by Emmanuel S. Antonarakis and Justin Hwang at the University of Minnesota’s Department of Medicine and the Masonic Cancer Center, sheds new light on the molecular underpinnings of aggressive prostate cancer phenotypes, offering potential avenues for therapeutic intervention.
Prostate cancer remains a leading cause of cancer-related morbidity and mortality globally, particularly in advanced stages where resistance to conventional androgen receptor-targeting therapies emerges. Approximately 30 to 40 percent of advanced prostate tumors exhibit basal-like gene expression programs, which are often linked to poor prognosis. Additionally, stem cell-like (SCL) tumor states have been implicated as a major mechanism by which tumors evade androgen receptor-targeted treatments, highlighting the urgent need for deeper molecular insights.
Through integrative transcriptomic analyses encompassing both primary prostate cancer (n=493) and castration-resistant prostate cancer (CRPC) cohorts (n=208), the researchers established a robust correlation between elevated CREB5 expression and the activation of basal-like and stem cell-associated gene signatures. This suggests that CREB5 operates at the nexus of transcriptional networks that endow tumor cells with stem-like properties and aggressive behavior.
Biochemical assays and chromatin immunoprecipitation sequencing (ChIP-seq) further revealed that CREB5 directly interacts with AP-1 family transcription factors, such as FOS and JUN, binding regulatory elements of AP-1 genes. This interaction amplifies oncogenic transcriptional cascades that foster tumor progression and cellular plasticity, key hallmarks of metastatic and therapy-resistant prostate cancer.
Functional experiments underscored the oncogenic potential of CREB5. Forced overexpression of CREB5 in prostate cancer cell lines resulted in enhanced colony formation in vitro and accelerated tumor growth in xenograft models, unequivocally demonstrating its tumor-promoting capabilities. Conversely, CREB5 knockdown impaired tumorigenicity, indicating the transcription factor’s essential role in maintaining aggressive cancer phenotypes.
Notably, the study’s analysis extended to comparing the expression of androgen receptor splice variant AR-V7 in CRPC tumors stratified by CREB5 levels. High CREB5 expression was associated with increased AR-V7, a marker of resistance to androgen deprivation therapies, suggesting a coordinated mechanism by which CREB5 contributes to therapeutic evasion and disease progression.
Genomic profiling also revealed that tumors with elevated CREB5 harbor distinct somatic alterations, further distinguishing them from low CREB5-expressing tumors. These genetic differences likely synergize with CREB5-driven transcriptional programs to potentiate malignant transformation and metastatic dissemination.
The findings highlight CREB5 not just as a passive biomarker but as a central driver orchestrating transcriptional states that endow tumor cells with plasticity and stemness, thereby promoting tumor aggressiveness. This positions CREB5 as a promising therapeutic target, particularly in androgen receptor-independent prostate cancer variants that currently lack effective treatments.
The research team advocates for the development of novel interventions aiming to disrupt CREB5 activity or its downstream effectors, potentially overcoming resistance mechanisms and improving outcomes for patients with advanced prostate cancer. Future studies are warranted to elucidate the precise molecular pathways mediated by CREB5 and to assess the efficacy of CREB5 inhibition in preclinical and clinical settings.
This study delineates a critical molecular axis in prostate cancer biology, connecting CREB5-regulated transcriptional programs with basal-like and stem cell-like tumor phenotypes. Its implications extend beyond fundamental cancer biology, offering a conceptual framework for combating therapy resistance and tumor progression via targeted disruption of transcription factor networks.
In conclusion, the elucidation of CREB5 as a master regulator of aggressive prostate cancer phenotypes underscores the complexity of tumor transcriptional landscapes and emphasizes the importance of transcriptional plasticity in cancer evolution. Through such insights, the cancer research community gains a new molecular target that may revolutionize therapeutic strategies for prostate cancer.
DOI: https://doi.org/10.18632/oncotarget.28826
Correspondence: Emmanuel S. Antonarakis – anton401@umn.edu, Justin Hwang – jhwang@umn.edu
Subject of Research: Cells
Article Title: CREB5 regulates stem cell-like transcriptional programs to enhance tumor progression in prostate cancer
News Publication Date: 17-Mar-2026
Web References: https://doi.org/10.18632/oncotarget.28826
Image Credits: © 2026 Makovec et al. Distributed under CC BY 4.0
Keywords: cancer, prostate cancer, CREB5, basal-like, stem cell-like, AP-1 transcription factors
