title: PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway.
abstract: The tumor suppressor protocadherin-10 (PCDH10) gene is important in cell proliferation, survival, apoptosis and migration. Inactivation of PCDH10 by promoter methylation is a frequent pathogenetic event in multiple myeloma (MM). The Wnt/β-catenin pathway is known to be involved in the cell growth of various types of cancer, including MM. However, the relationship between PCDH10 and Wnt signaling in MM remains unclear. In this study, we found that PCDH10 deficiency highly enhanced MM cell proliferation, Wnt signaling and the expression of BCL-9, an essential coactivator of Wnt transcriptional activity that is correlated with cell growth, survival and drug resistance. Restoration of PCDH10 suppressed nuclear localization of β-catenin, the activity of LEF/TCF, the expression of BCL-9 and AKT, whereas the expression of GSK3β was increased. The antagonistic effect of PCDH10 was associated with G1-phase blockage. Collectively, PCDH10 antagonized MM cell proliferation via the downregulation of Wnt/β-catenin/BCL-9 signaling, whereas PCDH10 repressed the expression of AKT to promote the expression of GSK3β and then to restrain the activation of β-catenin. Thus, the results offer a novel preclinical rationale in order to explore PCDH10 as an effective and selective therapeutic strategy to eradicate MM cells.
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Zesong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Haiting
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Hematology, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Hematology, Chongqing Three Gorges Central Hospital, Chongqing, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics; D011401:Promoter Regions, Genetic; D000091363:Protocadherins; D014157:Transcription Factors; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C111180:BCL9 protein, human; D015820:Cadherins; D009363:Neoplasm Proteins; C438603:PCDH10 protein, human; D000091363:Protocadherins; D014157:Transcription Factors; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3