title: The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover.
abstract: The androgen receptor (AR) is a key molecule involved in prostate cancer (PC) development and progression. Post-translational modification of the AR by co-regulator proteins can modulate its transcriptional activity. To identify which demethylases might be involved in AR regulation, an siRNA screen was performed to reveal that the demethylase, KDM4B, may be an important co-regulator protein. KDM4B enzymatic activity is required to enhance AR transcriptional activity; however, independently of this activity, KDM4B can enhance AR protein stability via inhibition of AR ubiquitination. Importantly, knockdown of KDM4B in multiple cell lines results in almost complete depletion of AR protein levels. For the first time, we have identified KDM4B to be an androgen-regulated demethylase enzyme, which can influence AR transcriptional activity not only via demethylation activity but also via modulation of ubiquitination. Together, these findings demonstrate the close functional relationship between AR and KDM4B, which work together to amplify the androgen response. Furthermore, KDM4B expression in clinical PC specimens positively correlates with increasing cancer grade (P < 0.001). Consequently, KDM4B is a viable therapeutic target in PC.
authors: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Kelly
authors: K
authors: Coffey
authors: Lynsey
authors: L
authors: Rogerson
authors: Claudia
authors: C
authors: Ryan-Munden
authors: Dhuha
authors: D
authors: Alkharaif
authors: Jacqueline
authors: J
authors: Stockley
authors: Rakesh
authors: R
authors: Heer
authors: Kanagasabai
authors: K
authors: Sahadevan
authors: Daniel
authors: D
authors: O'Neill
authors: Dominic
authors: D
authors: Jones
authors: Steven
authors: S
authors: Darby
authors: Peter
authors: P
authors: Staller
authors: Alejandra
authors: A
authors: Mantilla
authors: Luke
authors: L
authors: Gaughan
authors: Craig N
authors: CN
authors: Robson
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: D000728:Androgens; D006657:Histones; D011944:Receptors, Androgen; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human