title: Transcriptional repression of Bim by a novel YY1-RelA complex is essential for the survival and growth of Multiple Myeloma.
abstract: Multiple Myeloma (MM) is an incurable plasma cell cancer that is caused by several chromosomal translocations and gene deletions. Although deregulation of several signaling pathways including the Nuclear Factor-Kappa B (NF-κB) pathway has been reported in MM, the molecular requirement and the crosstalk between NF-κB and its target genes in MM cell survival has been largely unclear. Here, we report that Yin Yang1 (YY1), a target gene for NF-κB, is hyperexpressed in most MM tumor cells obtained from human patients, exhibits constitutive nuclear localization, and is essential for survival of MM cells. Mechanistically, we report a novel YY1-RelA complex formation, which is essential to transcriptionally repress a proapoptotic gene Bim. In line with this, depletion of YY1 or RelA resulted in elevated levels of Bim and apoptosis. Moreover, both YY1 and RelA are recruited to the Bim promoter and are required to repress the Bim promoter. Importantly, depletion of YY1 or RelA almost completely impaired the colony forming ability of MM progenitor cells suggesting that both RelA and YY1 are essential for the survival and growth of MM progenitor cells. Moreover, depletion of either YY1 or RelA completely inhibited MM tumor growth in xenograft models for human myeloma. Thus, a novel RelA-YY1 transcriptional repression complex is an attractive drug target in MM.
authors.affiliation: Department of Cancer and Cell Biology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Veena
authors.initials: V
authors.lastname: Potluri
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Noothi
authors.forename: Subrahmanya D
authors.initials: SD
authors.lastname: Vallabhapurapu
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Yoon
authors.forename: James J
authors.initials: JJ
authors.lastname: Driscoll
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lawrie
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Vallabhapurapu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D046912:Multiprotein Complexes / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D050986:YY1 Transcription Factor / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D050986:YY1 Transcription Factor; C494698:YY1 protein, human