PLX200015

GSE134147: MUC1-C ACTIVATES THE NURD COMPLEX IN DEDIFFERENTIATION OF TRIPLE-NEGATIVE BREASTCANCER CELLS

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4 and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic MUC1-C protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC) cells. However, there is no known link between MUC1-C and chromatin remodeling complexes. The present studies demonstrate that MUC1-C binds directly to the MYC HLH/LZ domain. In turn, we identified a previously unrecognized MUC1-CMYC pathway that regulates the NuRD complex. We show that MUC1-C/MYC complexes selectively activate the MTA1 and MBD3 genes and posttranscriptionally induce CHD4 expression in basal- and not luminal-type BC cells. The results further show that MUC1-C forms complexes with these NuRD components on the ESR1 promoter. In this way, silencing MUC1-C (i) decreased MTA1/MBD3/CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, and (ii) induced ESR1 expression and downstream estrogen response pathways. We also demonstrate that targeting MUC1-C and these NuRD components induces expression of FOXA1, GATA3 and other markers associated with the luminal phenotype. These findings and results from gain-of-function studies support a model in which MUC1-C activates the NuRD complex in driving luminalbasal dedifferentiation and plasticity of TNBC cells. SOURCE: Qiang Hu (Qiang.Hu@RoswellPark.org) - Roswell Park Cancer Institute