Loss of negative regulation by HDAC1 and REST contributes to MAD1 overexpression in breast cancer.

Abstract

Mitotic arrest deficient 1 (MAD1), an essential component of the mitotic spindle assembly checkpoint, is commonly overexpressed in breast cancers where it serves as a marker of poor prognosis. MAD1 overexpression is sufficient to permit nontransformed cells to form orthotopic mammary tumors and to promote tumorigenesis in a recently described mouse model with inducible expression of endogenous Mad1. However, the mechanism of MAD1 up-regulation in cancer is unclear. Here, we report a 440-bp region of the MAD1L1 promoter that confers a repressive phenotype on MAD1L1 transcription. Bioinformatics analysis implicated histone deacetylase 1 (HDAC1) in MAD1L1 transcriptional regulation. Consistent with this, HDAC1 localizes to the MAD1L1 promoter and HDAC inhibition increases MAD1 mRNA and protein expression. The MAD1L1-repressive region contains a partial binding site for RE1-silencing transcription factor (REST), which utilizes HDAC1 as a cofactor. REST overexpression decreases MAD1 expression. Moreover, breast cancer patient samples show a significant negative correlation between REST and MAD1L1 mRNA expression. These results support a model in which an altered transcriptional program downstream of loss of the tumor-suppressor REST, which normally represses MAD1L1 transcription by recruiting HDAC1-containing repressive complexes, contributes to MAD1 overexpression in breast cancer.