LKB1 catalytic activity contributes to estrogen receptor alpha signaling.
The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome (PJS) and in epithelial cancers, including hormone-sensitive organs such as breast, ovaries, testes, and prostate. Clinical studies in breast cancer patients show low LKB1 expression is related to poor prognosis, whereas in PJS, the risk of breast cancer is similar to the risk from germline mutations in breast cancer (BRCA) 1/BRCA2. In this study, we investigate the role of LKB1 in estrogen receptor alpha (ERalpha) signaling. We demonstrate for the first time that LKB1 binds to ERalpha in the cell nucleus in which it is recruited to the promoter of ERalpha-responsive genes. Furthermore, LKB1 catalytic activity enhances ERalpha transactivation compared with LKB1 catalytically deficient mutants. The significance of our discovery is that we demonstrate for the first time a novel functional link between LKB1 and ERalpha. Our discovery places LKB1 in a coactivator role for ERalpha signaling, broadening the scientific scope of this tumor suppressor kinase and laying the groundwork for the use of LKB1 as a target for the development of new therapies against breast cancer.
Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
Suchita
S
Nath-Sain
Paola A
PA
Marignani
D000091162:AMP-Activated Protein Kinase Kinases; D015153:Blotting, Western; D002384:Catalysis; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D000091162:AMP-Activated Protein Kinase Kinases; D004958:Estradiol; D047628:Estrogen Receptor alpha; D005982:Glutathione Transferase; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C109790:STK11 protein, human