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1.
Leukemia ; 31(12): 2780-2790, 2017 12.
Article in English | MEDLINE | ID: mdl-28555079

ABSTRACT

The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.


Subject(s)
B7-H1 Antigen/genetics , Gene Expression Regulation, Leukemic , MicroRNAs/genetics , Mucin-1/metabolism , Animals , B7-H1 Antigen/metabolism , Cell Line, Tumor , Humans , Immunomodulation/genetics , Mice , Mucin-1/genetics , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Transcriptional Activation , Up-Regulation
2.
Oncogene ; 36(28): 4037-4046, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28288138

ABSTRACT

Immunotherapeutic approaches, particularly programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade, have improved the treatment of non-small-cell lung cancer (NSCLC), supporting the premise that evasion of immune destruction is of importance for NSCLC progression. However, the signals responsible for upregulation of PD-L1 in NSCLC cells and whether they are integrated with the regulation of other immune-related genes are not known. Mucin 1 (MUC1) is aberrantly overexpressed in NSCLC, activates the nuclear factor-κB (NF-κB) p65→︀ZEB1 pathway and confers a poor prognosis. The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of NF-κB→︀ZEB1 signaling represses the TLR9 (toll-like receptor 9), IFNG, MCP-1 (monocyte chemoattractant protein-1) and GM-CSF genes, and that this signature is associated with decreases in overall survival. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.


Subject(s)
B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung , Immunity, Cellular/genetics , Lung Neoplasms , Mucin-1/physiology , Tumor Escape/genetics , A549 Cells , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Mice , Mice, Nude , Signal Transduction/genetics , Signal Transduction/immunology
3.
Oncogene ; 36(20): 2791-2801, 2017 05 18.
Article in English | MEDLINE | ID: mdl-27893710

ABSTRACT

B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→︀BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16INK4a expression. In support of these results, analysis of three gene expresssion data sets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing.


Subject(s)
Mucin-1/metabolism , Neoplasms/metabolism , Polycomb Repressive Complex 1/metabolism , Amino Acid Motifs , Amino Acid Sequence , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Regulation, Neoplastic , Gene Silencing , Histones/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Mucin-1/chemistry , Mucin-1/genetics , NF-kappa B/metabolism , Neoplasms/genetics , Promoter Regions, Genetic , Protein Binding , Protein Interaction Domains and Motifs , Proto-Oncogene Proteins c-myc/metabolism , Transcription, Genetic , Ubiquitination
4.
Oncogene ; 35(50): 6439-6445, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27212035

ABSTRACT

Aberrant expression of the DNA methyltransferases (DNMTs) and disruption of DNA methylation patterns are associated with carcinogenesis and cancer cell survival. The oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however, there is no known link between MUC1-C and DNA methylation. Our results demonstrate that MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b promoters in complexes with NF-κB p65 and drives DNMT1 and DNMT3b transcription. In this way, MUC1-C controls global DNA methylation as determined by analysis of LINE-1 repeat elements. The results further demonstrate that targeting MUC1-C downregulates DNA methylation of the CDH1 tumor suppressor gene in association with induction of E-cadherin expression. These findings provide compelling evidence that MUC1-C is of functional importance to induction of DNMT1 and DNMT3b and, in turn, changes in DNA methylation patterns in cancer cells.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases/physiology , DNA Methylation , Mucin-1/physiology , Neoplasms/genetics , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/genetics , Epithelial-Mesenchymal Transition , Humans , MCF-7 Cells , Transcription Factor RelA/physiology , DNA Methyltransferase 3B
5.
Oncogene ; 34(40): 5187-97, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-25659581

ABSTRACT

The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-ß-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1(+/-)/IL-10(-/-) mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1NF-κB pathway, downregulates BCL-XL and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1NF-κB signaling contributes to intestinal inflammation and colon cancer progression.


Subject(s)
Colonic Neoplasms/pathology , Gene Expression Regulation, Neoplastic/physiology , MAP Kinase Kinase Kinases/metabolism , Mucin-1/metabolism , Signal Transduction/physiology , Animals , Cell Line, Tumor , Chromatin Immunoprecipitation , Colonic Neoplasms/metabolism , Colonic Neoplasms/mortality , Disease Progression , Humans , Immunoblotting , Immunoprecipitation , Kaplan-Meier Estimate , Mice , Mice, Inbred C57BL , Mice, Transgenic , NF-kappa B/metabolism , Polymerase Chain Reaction , Proportional Hazards Models
6.
Blood Cancer J ; 4: e229, 2014 Jul 18.
Article in English | MEDLINE | ID: mdl-25036800

ABSTRACT

Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2-4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Buthionine Sulfoximine/pharmacology , Melphalan/pharmacology , Multiple Myeloma/drug therapy , Animals , Apoptosis/drug effects , Disease-Free Survival , Drug Synergism , Female , Humans , Mice , Mice, Nude , Multiple Myeloma/pathology , Random Allocation , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
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