biostudies-literatureAl-Nakouzi NGouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training CentreNCI NIH HHSMitacsProstate Cancer CanadaCIHR4760https://www.ebi.ac.uk/biostudies/studies/S-EPMC9376089biostudies-literatureUnknown13(1)Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitiNature communicationsReformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer.PMC9376089RS2014-02IT06057PJT-153092P50 CA097186Al-Nakouzi NWang CKEsko JDFazli LAdomat HEsfandnia SGustavsson TClausen TMNelson PSWang YCorey EDaugaard MLallous NLo JGleave MESalanti AHui DKhazamipour NDagil RChauchereau ACollins CChoudhary STruong SSpliid CBOo HZNelepcu IfalseReformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer.Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroiti2022-01-01T00:00:00Z2022 Aug2026-05-09T14:09:07.51Z2025-04-04T08:01:40.652ZS-EPMC93760893596385210.1038/s41467-022-32530-7