title: MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling.
abstract: The MST1 serine-threonine kinase, a component of the RASSF1-LATS tumor suppressor network, is involved in cell proliferation and apoptosis and has been implicated in cancer. However, the physiologic role of MST1 in prostate cancer (PCa) is not well understood. Here, we investigated the possibility of a biochemical and functional link between androgen receptor (AR) and MST1 signaling. We showed that MST1 forms a protein complex with AR and antagonizes AR transcriptional activity as shown by coimmunoprecipitation (co-IP), promoter reporter analysis, and molecular genetic methods. In vitro kinase and site-specific mutagenesis approaches indicate that MST1 is a potent AR kinase; however, the kinase activity of MST1 and its proapoptotic functions were shown not to be involved in inhibition of AR. MST1 was also found in AR-chromatin complexes, and enforced expression of MST1 reduced the binding of AR to a well-characterized, androgen-responsive region within the prostate-specific antigen promoter. MST1 suppressed PCa cell growth in vitro and tumor growth in mice. Because MST1 is also involved in regulating the AKT1 pathway, this kinase may be an important new link between androgenic and growth factor signaling and a novel therapeutic target in PCa.
authors.affiliation: Department of Medicine-Hematology/Oncology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, University of California, Los Angeles, California 90048, USA. bekir.cinar@cshs.org
authors.forename: Bekir
authors.initials: B
authors.lastname: Cinar
authors.forename: Filiz Kisaayak
authors.initials: FK
authors.lastname: Collak
authors.forename: Delia
authors.initials: D
authors.lastname: Lopez
authors.forename: Seckin
authors.initials: S
authors.lastname: Akgul
authors.forename: Nishit K
authors.initials: NK
authors.lastname: Mukhopadhyay
authors.forename: Murat
authors.initials: M
authors.lastname: Kilicarslan
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Gioeli
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D019556:COS Cells; D020169:Caspases / Q000502:physiology*; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction; D000099317:Hippo Kinases
chemical_list: D059002:Androgen Receptor Antagonists; D020169:Caspases; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; C095566:STK4 protein, human; D000099317:Hippo Kinases; C494918:AKT1 protein, human