title: Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer.
abstract: The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.forename: Kexin
authors.initials: K
authors.lastname: Xu
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.forename: Zhong
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authors.lastname: Chen
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Hongyun
authors.initials: H
authors.lastname: Wang
authors.forename: Mathieu
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authors.lastname: Lupien
authors.forename: Tao
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authors.lastname: Wu
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Meyer
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.forename: Arjun Kumar
authors.initials: AK
authors.lastname: Manrai
authors.forename: Olli A
authors.initials: OA
authors.lastname: Jänne
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: Rohit
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authors.lastname: Mehra
authors.forename: Bo
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authors.lastname: Han
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Lawrence
authors.initials: L
authors.lastname: True
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Christopher
authors.initials: C
authors.lastname: Fiore
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D000728:Androgens / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D011944:Receptors, Androgen; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes