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

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

doi:10.1038/s41388-019-0940-1

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.

Highlights

The RAS Association Domain Family 1A (RASSF1A) tumor suppressor gene (TSG) is localized to a region in chromosome 3 (3p21.3) that is deleted in human lung and certain other cancers [1, 2]
We found that MUC1-C and ZEB1 are detectable on RASSF1A intron 1 (Fig. 2f) and that MUC1-C silencing decreases the occupancy of ZEB1 in this region (Fig. 2g)
Studies in normal human mammary epithelial cells identified a role for the Sp1 transcription factor in activation of the RASSF1A promoter, such that decreases in Sp1 occupancy were associated with downregulation of RASSF1A expression [48]

Summary

Introduction

The RAS Association Domain Family 1A (RASSF1A) tumor suppressor gene (TSG) is localized to a region in chromosome 3 (3p21.3) that is deleted in human lung and certain other cancers [1, 2]. RASSF1A expression is repressed in diverse cancers by promoter hypermethylation [3, 4]. RASSF1A is one of the most frequently downregulated TSGs in human cancers [5,6,7,8]. RASSF1A forms a complex with KRAS and regulates multiple downstream effectors, including suppression of the canonical RAF→MEK→ERK pathway [8,9,10].

Methods

Results

Conclusion