Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

Abstract

SUMMARY While the multiple endocrine neoplasia type 1 (MEN1) gene functions as a tumor suppressor in a variety of cancer types, we explored its oncogenic role in breast tumorigenesis. The MEN1 gene product menin is involved in H3K4 trimethylation and co-activates transcription. We integrated ChIP-seq and RNA-seq data to identify menin target genes. Our analysis revealed that menin-dependent target gene promoters display looping to distal enhancers that are bound by menin, FOXA1 and GATA3. In this fashion, MEN1 co-regulates a proliferative breast cancer-specific gene expression program in ER+ cells. In primary mammary cells MEN1 exerts an anti-proliferative function by regulating a distinct expression signature. Our findings clarify the cell type-specific functions of MEN1 and inform the development of menin-directed treatments for breast cancer.

Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1

“…Menin has been reported to interact with several FOX family members including FOXN1/checkpoint suppressor 1 (CHES1) and FOXO1 (Busygina and Bale 2006; Wuescher, et al 2011). In sporadic breast cancer cells, menin is enriched at enhancers that contain FOXA1 binding motifs (Dreijerink, et al 2017). In mouse embryonic stem cell (mESC)-derived embryoid bodies, lower Foxa1 and Foxa2 mRNA levels were observed in the absence of Men1 gene expression (Zhang, et al 2011).…”

“…This interaction is important for transcription of ERα target genes through recruitment of H3K4me3 methyltransferase activity. Menin also regulates transcription of the ESR1 gene, which encodes ERα in breast cancer and pituitary cells (Dreijerink et al 2017). Subsequent work showed that menin is a generic co-regulator for nuclear receptor-mediated transcription as it interacts with many other NR family members including the vitamin D receptor (VDR), the retinoid X receptor (RXR), the peroxisome proliferator-activated receptors (PPAR) alpha and gamma, the liver X receptor (LXR) alpha and the androgen receptor (AR) (Cheng, et al 2015; Cheng, et al 2011; Dreijerink et al 2006; Dreijerink, et al 2009a; Malik, et al 2015).…”

“…In accordance with previous studies, only a limited number of genes fullfilled these requirements. Menin-MLL1/MLL2 target genes not only had menin bound at their TSS, but also showed an enrichment of menin binding to distal enhancer sites that showed looping to the target gene TSS (Dreijerink et al 2017). From these observations it can be concluded that not only the presence of menin at TSS, but rather the combination of the presence of menin at TSS and enhancer sites, determines target gene specificity of menin-MLL1/MLL2 complexes.…”

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

“…The mechanisms of cancer-related elimination or reduction of tumor suppressor proteins include transcriptional repression of the genes, degradation of proteins, and posttranslational modifications that change biological activities of these proteins (1,3,4). A number of recent papers showed that certain proteins work as oncoproteins and as tumor suppressors depending on cell environment, target genes, and posttranslational modifications (5)(6)(7)(8)(9)(10)(11)(12). In this regard, Dreijerink et al have recently shown that menin tumor suppressor protein displays its tumor suppression activity in a variety of cancer cells; however, it possesses oncogenic activities in breast tumorigenesis (5).…”

“…A number of recent papers showed that certain proteins work as oncoproteins and as tumor suppressors depending on cell environment, target genes, and posttranslational modifications (5)(6)(7)(8)(9)(10)(11)(12). In this regard, Dreijerink et al have recently shown that menin tumor suppressor protein displays its tumor suppression activity in a variety of cancer cells; however, it possesses oncogenic activities in breast tumorigenesis (5). Another recent report revealed that the Kruppelassociated box zinc finger protein ZNF224 can behave as an oncoprotein and as a tumor suppressor protein and that these opposite activities of ZNF224 are controlled by specific protein-protein interactions (6).…”