title: Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas.
abstract: Dysregulation of MYC expression is a hallmark of cancer, but the development of agents that target MYC has remained challenging. The oncogenic MUC1-C transmembrane protein is, like MYC, aberrantly expressed in diverse human cancers. The present studies demonstrate that MUC1-C induces MYC expression in KRAS mutant non-small cell lung cancer (NSCLC) cells, an effect that can be suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or pharmacologic inhibition with GO-203. MUC1-C activated the WNT/β-catenin (CTNNB1) pathway and promoted occupancy of MUC1-C/β-catenin/TCF4 complexes on the MYC promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase (EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene transcription. We also show that targeting MUC1-C decreased the expression of key MYC target genes essential for the growth and survival of NSCLC cells, such as TERT and CDK4. Based on these results, we found that the combination of GO-203 and the BET bromodomain inhibitor JQ1, which targets MYC transcription, synergistically suppressed MYC expression and cell survival in vitro as well as tumor xenograft growth. Furthermore, MUC1 expression significantly correlated with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken together, these findings suggest a therapeutic approach for targeting MYC-dependent cancers and provide the framework for the ongoing clinical studies addressing the efficacy of MUC1-C inhibition in solid tumors.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bouillez
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Sean
authors.initials: S
authors.lastname: Pitroda
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Caining
authors.initials: C
authors.lastname: Jin
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Akriti
authors.initials: A
authors.lastname: Kharbanda
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ashujit
authors.initials: A
authors.lastname: Tagde
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. donald_kufe@dfci.harvard.edu.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008819:Mice, Nude; D018396:Mucin-1 / Q000235:genetics*; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; C117307:KRAS protein, human; C060192:MUC1 protein, human; D018396:Mucin-1; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
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