The LATS2/KPM tumor suppressor is a negative regulator of the androgen receptor.
The androgen receptor (AR) is a member of the steroid receptor superfamily that plays critical roles in the development and maintenance of the male reproductive system and in prostate cancer. Actions of AR are controlled by interaction with several classes of coregulators. In this study, we have identified LATS2/KPM as a novel AR-interacting protein. Human LATS1 and LATS2 are tumor suppressors that are homologs of Drosophila warts/lats. The interaction surface of LATS2 is mapped to the central region of the protein, whereas the AR ligand binding domain is sufficient for this interaction. LATS2 functions as a modulator of AR by inhibiting androgen-regulated gene expression. The mechanism of LATS2-mediated repression of AR activity appears to involve the inhibition of AR NH2- and COOH-terminal interaction. Chromatin immunoprecipitation assays in human prostate carcinoma cells reveal that LATS2 and AR are present in the protein complex that binds at the promoter and enhancer regions of prostate-specific antigen, and overexpression of LATS2 results in a reduction in androgen-induced expression of endogenous prostate-specific antigen mRNA. Immunohistochemistry shows that LATS2 and AR are localized within the prostate epithelium and that LATS2 expression is lower in human prostate tumor samples than in normal prostate. The results suggest that LATS2 may play a role in AR-mediated transcription and contribute to the development of prostate cancer.
Powzaniuk
Mark
M
Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA.
McElwee-Witmer
Sheila
S
Vogel
Robert L
RL
Hayami
Tadashi
T
Rutledge
Su Jane
SJ
Chen
Fang
F
Harada
Shun-Ichi
S
Schmidt
Azriel
A
Rodan
Gideon A
GA
Freedman
Leonard P
LP
Bai
Chang
C
D059002:Androgen Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D004742:Enhancer Elements, Genetic / Q000235:genetics; D006801:Humans; D008024:Ligands; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
D059002:Androgen Receptor Antagonists; D008024:Ligands; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D017430:Prostate-Specific Antigen