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Oncogene. 2019 Aug 21. doi: 10.1038/s41388-019-0940-1. [Epub ahead of print]

MUC1-C represses the RASSF1A tumor suppressor in human carcinoma cells.

Author information

1
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
2
Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
3
Genus Oncology, Boston, MA, USA.
4
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. donald_kufe@dfci.harvard.edu.

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.

PMID:
31435022
DOI:
10.1038/s41388-019-0940-1

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