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MUC1-C represses the RASSF1A tumor suppressor in human carcinoma cells
Hasan Rajabi1, Tsuyoshi Hata1, Wei Li1
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Abstract:
RASSF1A encodes a tumor suppressor that inhibits the RAS→RAF→MEK→ERK pathway and is one of the most frequently inactivated genes in human cancers. MUC1-C is an oncogenic effector of the cancer cell epigenome that is overexpressed in diverse carcinomas. We show here that MUC1-C represses RASSF1A expression in KRAS wild-type and mutant cancer cells. Mechanistically, MUC1-C occupies the RASSF1A promoter in a complex with the ZEB1 transcriptional repressor. In turn, MUC1-C/ZEB1 complexes recruit DNA methyltransferase 3b (DNMT3b) to the CpG island in the RASSF1A promoter. Targeting MUC1-C, ZEB1, and DNMT3b thereby decreases methylation of the CpG island and derepresses RASSF1A transcription. We also show that targeting MUC1-C regulates KRAS signaling, as evidenced by RNA-seq analysis, and decreases MEK/ERK activation, which is of importance for RAS-mediated tumorigenicity. These findings define a previously unrecognized role for MUC1-C in suppression of RASSF1A and support targeting MUC1-C as an approach for inhibiting MEK→ERK signaling.
Insights
MUC1-C oncogene represses the RASSF1A tumor suppressor gene by recruiting ZEB1 and DNMT3b to its promoter. Targeting MUC1-C reactivates RASSF1A, inhibits KRAS signaling, and reduces MEK/ERK activation in cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- RASSF1A is a tumor suppressor frequently inactivated in human cancers.
- MUC1-C is an oncogenic protein overexpressed in various carcinomas.
Purpose of the Study:
- To investigate the role of MUC1-C in regulating RASSF1A expression.
- To elucidate the molecular mechanisms by which MUC1-C represses RASSF1A.
- To explore the therapeutic potential of targeting MUC1-C in cancer.
Main Methods:
- Chromatin immunoprecipitation assays to detect MUC1-C/ZEB1/DNMT3b complex at the RASSF1A promoter.
- DNA methylation analysis of the RASSF1A CpG island.
- RNA-sequencing (RNA-seq) to assess KRAS signaling pathway changes.
- Western blotting to evaluate MEK/ERK activation.
Main Results:
- MUC1-C directly represses RASSF1A expression in both KRAS wild-type and mutant cancer cells.
- MUC1-C forms a complex with ZEB1, which recruits DNMT3b to methylate and silence the RASSF1A promoter.
- Targeting MUC1-C, ZEB1, and DNMT3b leads to decreased RASSF1A promoter methylation and restored RASSF1A transcription.
- Targeting MUC1-C modulates KRAS signaling and reduces MEK/ERK pathway activation.
Conclusions:
- MUC1-C plays a critical role in suppressing RASSF1A expression through epigenetic mechanisms.
- The MUC1-C/ZEB1/DNMT3b complex is a key regulator of RASSF1A silencing in cancer.
- Targeting MUC1-C offers a potential therapeutic strategy to reactivate RASSF1A and inhibit oncogenic signaling pathways like MEK/ERK.
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