title: MUC1-C drives MYC in multiple myeloma.
abstract: Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples. The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein. The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a β-catenin/transcription factor 4 (TCF4)-mediated mechanism. In this way, MUC1-C (1) increases β-catenin occupancy on the MYC promoter, (2) forms a complex with β-catenin and TCF4, and, in turn, (3) drives MYC transcription. Analysis of MM cells using quantitative real-time reverse transcription polymerase chain reaction arrays further demonstrated that silencing MUC1-C is associated with downregulation of MYC target genes, including CCND2, hTERT, and GCLC Analysis of microarray data sets further demonstrated that MUC1 levels positively correlate with MYC expression in MM progression and in primary cells from over 800 MM patients. These findings collectively provide convincing evidence that MUC1-C drives MYC expression in MM.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Ashujit
authors.initials: A
authors.lastname: Tagde
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bouillez
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Department of Biomedical Informatics, and.
authors.forename: Reddy
authors.initials: R
authors.lastname: Gali
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bailey
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D056742:Cyclin D2 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018396:Mucin-1 / Q000096:biosynthesis* / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; C060192:MUC1 protein, human; C489427:MYC protein, human; D018396:Mucin-1; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; C509186:TERT protein, human; D019098:Telomerase; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase