Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52

Abstract

Castration‐resistant prostate cancer (CRPC) is the emergence of prostate cancer cells that have adapted to the androgen‐depleted environment of the prostate. In recent years, targeting multiple chaperones and co‐chaperones (e.g., Hsp27, FKBP52) that promote androgen receptor (AR) signaling and/or novel AR regulatory mechanisms have emerged as promising alternative treatments for CRPC. We have shown that inactivation of inhibitor of differentiation 4 (ID4), a dominant‐negative helix loop helix protein, promotes de novo steroidogenesis and CRPC with a gene expression signature that resembles constitutive AR activity in castrated mice. In this study, we investigated the underlying mechanism through which loss of ID4 potentiates AR signaling. Proteomic analysis between prostate cancer cell line LNCaP (L+ns) and LNCaP lacking ID4 (L(−)ID4) revealed elevated levels of Hsp27 and FKBP52, suggesting a role for these AR‐associated co‐chaperones in promoting constitutively active AR signaling in L(−)ID4 cells. Interestingly, protein interaction studies demonstrated a direct interaction between ID4 and the 52‐kDa FK506‐binding protein (FKBP52) in vitro, but not with AR. An increase in FKBP52‐dependent AR transcriptional activity was observed in L(−)ID4 cells. Moreover, pharmacological inhibition of FKBP52‐AR signaling, by treatment with MJC13, attenuated the tumor growth, weight, and volume in L(−)ID4 xenografts. Together, our results demonstrate that ID4 selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52‐mediated AR signaling.

Construction and Validation of a 13-Gene Signature for Prognosis Prediction in Medulloblastoma

“…FKBP4 was found to be associated with major depressive disorder (Binder et al, 2004;Tatro et al, 2009a,b) and might be critical to early steps in neuronal differentiation (Quintá and Galigniana, 2012), chemotropic guidance of neuronal growth cones (Shim et al, 2009), and regulating neuroprotective activities with calcium channels (Ruan et al, 2008). It was also reported in malignancies like prostate cancer (Bhowal et al, 2017;Joshi et al, 2017) and breast cancer (Ostrow et al, 2009). CCNY knockout can inhibit glioma cell proliferation (Xu et al, 2010).…”

FKBP Ligands—Where We Are and Where to Go?

“…This hormone receptor activity makes FKBP52 an interesting target in hormone-driven tumors like prostate cancer, colorectal adenocarcinomas, breast cancer, and myelomas (Storer et al, 2011; Storer Samaniego et al, 2015). Recently, Joshi et al were able to prove an interaction between FKBP52 and inhibitor of differentiation 4 (ID4) in castration-resistant prostate cancer (CRPR) in vitro (Joshi et al, 2017). In this type of cancer, prostate cancer cells adapt to the androgen-depleted environment of the prostate.…”

Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52

“…The analysis of needle prostate biopsies in humans revealed that FKBP52 is indeed a useful and reliable biomarker of prostate cancer [91]. Its close-related partner FKBP51 is also overexpressed in this type of cancers and shows the ability to stimulate AR activity [93,94,95], the immunophilin being itself a product of the AR activity [96]. This generates a harmful feedback circuit that is worsened by the fact that FKBP51 impairs the biological activity of the GR.…”