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

Hasan Rajabi, Tsuyoshi Hata, Wei Li, Mark D. Long, Qiang Hu, Song Liu, Deepak Raina, Ling Kui, Yota Yasumizu, Deli Hong, Mehmet Samur, Donald Kufe

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5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7266-7277
Number of pages12
JournalOncogene
Volume38
Issue number47
DOIs
Publication statusPublished - 2019 Nov 21

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Rajabi, H., Hata, T., Li, W., Long, M. D., Hu, Q., Liu, S., Raina, D., Kui, L., Yasumizu, Y., Hong, D., Samur, M., & Kufe, D. (2019). MUC1-C represses the RASSF1A tumor suppressor in human carcinoma cells. Oncogene, 38(47), 7266-7277. https://doi.org/10.1038/s41388-019-0940-1