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MUC1-C activates BMI1 in human cancer cells
M Hiraki1, T Maeda1, A Bouillez1
1Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Oncogene
|November 29, 2016
Summary
The oncogenic MUC1-C subunit drives BMI1 expression in cancer cells, promoting cancer stem cell self-renewal. Targeting MUC1-C suppresses BMI1, leading to tumor suppressor gene activation and potential therapeutic strategies.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a key component of the polycomb repressive complex 1 (PRC1) and is overexpressed in various cancers, promoting cancer stem cell self-renewal.
- The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is also overexpressed in human carcinomas and linked to cancer cell self-renewal.
- No prior relationship between MUC1-C and BMI1 in cancer was established.
Purpose of the Study:
- To investigate the relationship between MUC1-C and BMI1 in cancer.
- To elucidate the mechanism by which MUC1-C influences BMI1 expression.
- To determine the functional consequences of the MUC1-C-BMI1 interaction on cancer cell biology and gene expression.
Main Methods:
- Utilized cancer cell lines (breast and others) to study gene expression and protein interactions.
- Investigated MYC-dependent transcription and microRNA regulation (miR-200c) of BMI1.
- Performed chromatin immunoprecipitation assays to assess BMI1 occupancy on target gene promoters (e.g., CDKN2A).
- Analyzed gene expression datasets to correlate MUC1-C and BMI1 levels in breast cancers.
Main Results:
- Demonstrated that MUC1-C drives BMI1 transcription via a MYC-dependent pathway.
- Showed that MUC1-C inhibits miR-200c-mediated repression of BMI1.
- Confirmed MUC1-C directly binds BMI1, promoting its occupancy on the CDKN2A promoter, leading to repression of the p16INK4a tumor suppressor.
- Targeting MUC1-C resulted in decreased BMI1 ubiquitylation, derepression of HOXC5 and HOXC13, and induction of p16INK4a expression.
- Found significant correlations between MUC1-C and BMI1 expression in human breast cancers.
Conclusions:
- Uncovered a novel pathway where MUC1-C drives BMI1 expression in cancer cells.
- Established a direct interaction between MUC1-C and BMI1, linking MUC1-C to PRC1 function in epigenetic gene silencing.
- Highlighted the MUC1-C-BMI1 axis as a potential therapeutic target for cancers characterized by their overexpression.
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