CREB5 regulates stem cell-like transcriptional programs to enhance tumor progression in prostate cancer

// Allison Makovec 1 , 2 , 3 , John T. Phoenix 4 , Hannah E. Bergom 1 , 2 , Ella Boytim 1 , 2 , Ava P. Gustafson 1 , 2 , Aiden Deacon 5 , Sydney Tape 6 , Atef Ali 7 , Megan Ludwig 2 , 8 , Samuel P. Pitzen 2 , 9 , David Moline 1 , 2 , Camden Richter 10 , Hudson Longie 1 , 2 , Mei-Chi Su 11 , Sampreeti Jena 11 , Pornlada Likasitwatanakul 1 , 12 , Justin M. Drake 2 , 8 , R. Stephanie Huang 2 , 11 , William C. Hahn 13 , 14 , Jonathan P. Rennhack 4 , Scott M. Dehm 2 , 15 , 16 , Steven Kregel 4 , Emmanuel S. Antonarakis 1 , 2 and Justin Hwang 1 , 2 1 Department of Medicine, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA 2 Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA 3 University of Kansas Medical Center, Kansas City, KS 66160, USA 4 Department of Cancer Biology, Loyola University Chicago, Chicago, IL 60153, USA 5 Cancer Biology Graduate Program, University of Colorado Anschutz, Aurora, CO 80045, USA 6 Medical College of Wisconsin, Green Bay, WI 54115, USA 7 Bioinformatic Interdepartmental Program, University of California, Los Angeles, CA 90095, USA 8 Department of Pharmacology, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA 9 Graduate Program in Molecular, Cellular, and Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55455, USA 10 Rush University Medical College, Chicago, IL 60612, USA 11 Department of Experimental and Clinical Pharmacology, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA 12 Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand 13 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 14 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA 15 Department of Laboratory Medicine and Pathology, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA 16 Department of Urology, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA Correspondence to: Emmanuel S. Antonarakis, email: [email protected] Justin Hwang, email: [email protected] Keywords: prostate cancer; CREB5; basal-like; stem cell-like; AP-1 transcription factors Received: July 21, 2025     Accepted: February 16, 2026     Published: March 17, 2026 Copyright: © 2026 Makovec et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Prostate gland cells can be transcriptionally and morphologically characterized as basal and luminal. About 30–40% of advanced prostate cancers (PC) harbor basal-like transcription programs. In castration-resistant PC (CRPC), studies indicate that basal and stem cell-like (SCL) tumors are major resistance mechanisms to androgen receptor (AR)-targeted therapies. SCL tumors have reduced AR activity and increased stem-cell activity that promotes tumor formation, which contributes to poor clinical outcomes. We determined that CREB5 is a key regulator of basal and SCL transcriptional programs and tumor-forming phenotypes in PC. Through in silico modeling of PC transcriptomes and several pre-defined PC signaling programs, CREB5 expression was best associated with basal-like gene signatures and SCL-associated genes in primary PC and CRPCs ( n = 493 and 208). This included associations with FOSL1 and other AP-1 transcription factors. We further found that CREB5 interacted with AP-1 proteins and bound to the regulatory elements of AP-1 genes, suggesting a mechanistic role in regulating the activity of AP-1 genes. In AR-positive cells, CREB5 overexpression promoted cell colony growth with tumorigenic properties and increased tumor size in vivo . These findings implicate CREB5 as a driver of the transcriptional programs underlying AR-independent basal and SCL CRPC subtypes, and this activity is detectable in primary PC.