title: Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.
abstract: The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity.
authors.affiliation: Department of Urology, Osaka Medical College, Osaka 569-8686, Japan; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Komura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Jeong
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hinohara
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Fangfang
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Department of Urology, Osaka Medical College, Osaka 569-8686, Japan;
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Gwo-Shu Mary
authors.initials: GS
authors.lastname: Lee
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065; kantoff@mskcc.org christopher_sweeney@dfci.harvard.edu.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Harvard Medical School, Boston, MA 02215 kantoff@mskcc.org christopher_sweeney@dfci.harvard.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D059014:High-Throughput Nucleotide Sequencing; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D056466:Histone Demethylases; C095561:KDM5D protein, human
keywords: JARID1D; KDM5D; androgen receptor; docetaxel; prostate cancer