Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas

Bouillez, Audrey; Rajabi, Hasan; Pitroda, Sean P.; Jin, Caining; Alam, Maroof; Kharbanda, Akriti; Tagde, Ashujit; Wong, Kwok-Kin; Küfe, Donald

doi:10.1158/0008-5472.can-15-1804

Cited by 78 publications

(95 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Soluble proteins were analyzed by immunoblotting with anti-MUC1-C antibody (Thermo Scientific), anti-DNMT1 (Abcam), anti-NF-κB p65 (Santa Cruz Biotechnology), anti-phospho-NF-κB p65, anti-IKKβ, anti-phospho-IKKβ, anti-E-cadherin, anti-PTEN (Cell Signaling), anti-BRCA1 (Santa Cruz Biotechnology) and anti-β-actin (Sigma). Detection of immune complexes was achieved using horseradish peroxidase-conjugated secondary antibodies and enhanced chemuluminescence (GE Healthcare, Piscataway, NJ) [45, 46]. …”

Section: Methodsmentioning

confidence: 99%

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

et al. 2016

Self Cite

View full text Add to dashboard Cite

Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML); however, the regulation of DNA methyltransferase 1 (DNMT1), which is responsible for maintenance of DNA methylation patterns, has largely remained elusive. MUC1-C is a transmembrane oncoprotein that is aberrantly expressed in AML stem-like cells. The present studies demonstrate that targeting MUC1-C with silencing or a pharmacologic inhibitor GO-203 suppresses DNMT1 expression. In addition, MUC1 expression positively correlates with that of DNMT1 in primary AML cells, particularly the CD34+/CD38− population. The mechanistic basis for this relationship is supported by the demonstration that MUC1-C activates the NF-κB p65 pathway, promotes occupancy of the MUC1-C/NF-κB complex on the DNMT1 promoter and drives DNMT1 transcription. We also show that targeting MUC1-C substantially reduces gene promoter-specific DNA methylation, and derepresses expression of tumor suppressor genes, including CDH1, PTEN and BRCA1. In support of these results, we demonstrate that combining GO-203 with the DNMT1 inhibitor decitabine is highly effective in reducing DNMT1 levels and decreasing AML cell survival. These findings indicate that (i) MUC1-C is an attractive target for the epigentic reprogramming of AML cells, and (ii) targeting MUC1-C in combination with decitabine is a potentially effective clinical approach for the treatment of AML.

show abstract

Section: Methodsmentioning

confidence: 99%

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…The oncogenic transmembrane protein MUC1-C transcribes the C-MYC mRNA and proteins, which in turn, upregulates the C-MYC gene expression. Upregulation of C-MYC genes leads to decrease of the Nrf2 stability (Tagde et al 2016a;Bouillez et al 2016). (e) Metabolic activation of Nrf2 by Kreb cycle intermediates: in Kreb's cycle, fumarate modifies cysteine residues within Keap1, which disrupt the ability to ubiquitinate Nrf2.…”

Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

View full text Add to dashboard Cite

The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

show abstract

“…18 Exposure to the MUC1 inhibitor results in downregulation of PD-L1 expression in primary AML cells and potentially renders them more susceptible to T-cell-mediated recognition and lysis. Investigators have begun to explore the use of microRNAs as therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

“…11–16 MUC1 interacts with the WNT/-catenin pathway and promotes the activation of WNT target genes, 17,18 NFΚ -B 19–21 and STAT1/3, 22,23 pathways critical for the proliferation and survival of tumor cells. In addition, MUC1 regulates pathways responsible for autonomous self-renewal 24 and is uniquely expressed on leukemia stem cells as compared to normal hematopoietic stem cells.…”

Section: Introductionmentioning

confidence: 99%

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas

Cited by 78 publications

References 49 publications

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

Contact Info

Product

Resources

About