TY - JOUR
T1 - CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies
AU - Hwang, Justin H.
AU - Arafeh, Rand
AU - Seo, Ji Heui
AU - Baca, Sylvan C.
AU - Ludwig, Megan
AU - Arnoff, Taylor E.
AU - Sawyer, Lydia
AU - Richter, Camden
AU - Tape, Sydney
AU - Bergom, Hannah E.
AU - McSweeney, Sean
AU - Rennhack, Jonathan P.
AU - Klingenberg, Sarah A.
AU - Cheung, Alexander T.M.
AU - Kwon, Jason
AU - So, Jonathan
AU - Kregel, Steven
AU - Van Allen, Eliezer M.
AU - Drake, Justin M.
AU - Freedman, Matthew L.
AU - Hahn, William C.
N1 - Publisher Copyright:
© 2022, Hwang, Arafeh, Seo et al.
PY - 2022/5
Y1 - 2022/5
N2 - Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins, we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein–protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found that CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance.
AB - Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins, we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein–protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found that CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance.
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U2 - 10.7554/eLife.73223
DO - 10.7554/eLife.73223
M3 - Article
C2 - 35550030
AN - SCOPUS:85131107812
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e73223
ER -