title: The ETS domain transcription factor ELK1 directs a critical component of growth signaling by the androgen receptor in prostate cancer cells.
abstract: The androgen receptor (AR) is essential for diverse aspects of prostate development and function. Molecular mechanisms by which prostate cancer (PC) cells redirect AR signaling to genes that primarily support growth are unclear. A systematic search for critical AR-tethering proteins led to ELK1, an ETS transcription factor of the ternary complex factor subfamily. Although genetically redundant, ELK1 was obligatory for AR-dependent growth and clonogenic survival in both hormone-dependent PC and castration-recurrent PC cells but not for AR-negative cell growth. AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions. AR functioned as a coactivator of ELK1 by association through its A/B domain, bypassing the classical mechanism of ELK1 activation by phosphorylation and without inducing ternary complex target genes. The ELK1-AR synergy per se was ligand-independent, although it required ligand for nuclear localization of AR as targeting the AR A/B domain to the nucleus recapitulated the action of hormone; accordingly, Casodex was a poor antagonist of the synergy. ELK3, the closest substitute for ELK1 in structure/function and genome recognition, did not interact with AR. ELK1 thus directs selective and sustained gene induction that is a substantial and critical component of growth signaling by AR in PC cells. The ELK1-AR interaction offers a functionally tumor-selective drug target.
authors: Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201-2013, USA.
authors: Mugdha
authors: M
authors: Patki
authors: Venkatesh
authors: V
authors: Chari
authors: Suneethi
authors: S
authors: Sivakumaran
authors: Mesfin
authors: M
authors: Gonit
authors: Robert
authors: R
authors: Trumbly
authors: Manohar
authors: M
authors: Ratnam
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014105:Tosyl Compounds / Q000494:pharmacology; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; C494112:ELK1 protein, human; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D050807:ets-Domain Protein Elk-1; C053541:bicalutamide