机构：[1]Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA[2]Department of Otolaryngology and Head and Neck Surgery, Affiliated Beijing Tongren Hospital, Capital University of Medical Sciences, Beijing 100730, China临床科室耳鼻咽喉-头颈外科首都医科大学附属北京同仁医院首都医科大学附属同仁医院[3]Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA[4]Departments of Biology and Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA[5]Eng.A.B Research Chair for Growth Factors and Bone Regeneration, Division of Periodontology, College of Dentistry, King Saud University, Riyadh 11545, Saudi Arabia[6]Division of Cellular & Molecular Biology, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, ON M5G 2M9, Canada
Abnormal activation of Wnt/beta-catenin-mediated transcription is associated with a variety of human cancers. Here, we report that LATS2 inhibits oncogenic Wnt/beta-catenin-mediated transcription by disrupting the beta-catenin/BCL9 interaction. LATS2 directly interacts with beta-catenin and is present on Wnt target gene promoters. Mechanistically, LATS2 inhibits the interaction between BCL9 and beta-catenin and subsequent recruitment of BCL9, independent of LATS2 kinase activity. LATS2 is downregulated and inversely correlated with the levels of Wnt target genes in human colorectal cancers. Moreover, nocodazole, an antimicrotubule drug, potently induces LATS2 to suppress tumor growth in vivo by targeting beta-catenin/BCL9. Our results suggest that LATS2 is not only a key tumor suppressor in human cancer but may also be an important target for anticancer therapy.
基金：
NICDR [DE015964, DE17684, DE13848]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA132134]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA132134] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [R01DE023874, R01DE015964, R37DE013848] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [R01DE017684, R01DE013848] Funding Source: NIH RePORTER
生物学