Menin enhances c-Myc-mediated transcription to promote cancer progression

Wu, Gongwei; Yuan, Mengqiu; Shen, Shengqi; Ma, Xiaoyu; Fang, Jingwen; Zhu, Lianbang; Sun, Linchong; Liu, Zhaoji; He, Xiaoping; Huang, De; Li, Tingting; Li, Chenchen; Wu, Jun; Hu, Xin; Li, Zhaoyong; Song, Libing; Qu, Kun; Zhang, Huafeng; Gao, Ping

doi:10.1038/ncomms15278

Cited by 42 publications

(40 citation statements)

References 64 publications

(118 reference statements)

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“…Menin has numerous MLL complex‐independent functions . Of particular relevance to this study, menin was shown to cooperate with cMYC in the regulation of metabolism‐associated genes, including PSAT1 , in an MLL‐independent fashion . Moreover, the EWS–FLI1 oncoprotein itself contributes to maintenance of SSP gene expression in Ewing sarcoma .…”

Section: Discussionmentioning

confidence: 79%

“…Alternatively, menin-dependent regulation of SSP gene expression may be mediated by non-trithorax-dependent mechanisms that involve other menin protein-binding partners. Menin has numerous MLL complex-independent functions [52][53][54][55][56]. Of particular relevance to this study, menin was shown to cooperate with cMYC in the regulation of metabolism-associated genes, including PSAT1, in an MLL-independent fashion [53].…”

Section: Inhibition Of Menin Leads To Reduced De Novo Serine and Glycmentioning

confidence: 80%

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Menin regulates the serine biosynthetic pathway in Ewing sarcoma

Svoboda

Teh

Sud

et al. 2018

The Journal of Pathology

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Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin-MLL interaction leads to loss of menin and MLL1 protein expression, and to inhibition of growth and tumorigenicity. Here, we have investigated the mechanistic basis of menin-MLL-mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bru-seq) was performed to identify changes in nascent gene transcription in Ewing sarcoma cells, following exposure to the menin-MLL interaction inhibitor MI-503. Menin-MLL inhibition resulted in early and widespread reprogramming of metabolic processes. In particular, the serine biosynthetic pathway (SSP) was the pathway most significantly affected by MI-503 treatment. Baseline expression of SSP genes and proteins (PHGDH, PSAT1, and PSPH), and metabolic flux through the SSP were confirmed to be high in Ewing sarcoma. In addition, inhibition of PHGDH resulted in reduced cell proliferation, viability, and tumor growth in vivo, revealing a key dependency of Ewing sarcoma on the SSP. Loss of function studies validated a mechanistic link between menin and the SSP. Specifically, inhibition of menin resulted in diminished expression of SSP genes, reduced H3K4me3 enrichment at the PHGDH promoter, and complete abrogation of de novo serine and glycine biosynthesis, as demonstrated by metabolic tracing studies with C-labeled glucose. These data demonstrate that the SSP is highly active in Ewing sarcoma and that its oncogenic activation is maintained, at least in part, by menin-dependent epigenetic mechanisms involving trithorax complexes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley& Sons, Ltd.

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Section: Discussionmentioning

confidence: 79%

Section: Inhibition Of Menin Leads To Reduced De Novo Serine and Glycmentioning

confidence: 80%

Menin regulates the serine biosynthetic pathway in Ewing sarcoma

Svoboda

Teh

Sud

et al. 2018

The Journal of Pathology

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“…In HEK293 embryonic kidney cells, menin and the mixed-lineage leukemia (MLL) complex were found to interact with the transcription factor FUSE binding protein 1 (FBP1/FUSBP1) to stimulate MYC expression (Zaman, et al 2014). It was recently reported, that in fibrosarcoma cells menin can also interact directly with MYC and regulate MYC target genes in an H3K4me3-independent manner (Wu, et al 2017). More in line with its tumor suppressive function, loss of menin was shown to result in upregulation of the c-Myc mRNA in mouse-derived pancreatic cells, possibly via increased Hedgehog signaling pathway activity (Gurung, et al 2013a).…”

Section: Menin Binds To Transcription Factorsmentioning

confidence: 99%

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

Dreijerink¹,

Timmers²,

Brown³

2017

Endocrine-Related Cancer

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Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin modifying enzymes, in particular the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin. We propose that menin regulates cell type-specific transcriptional programs by linking chromatin regulatory complexes to specific transcription factors. In this fashion, the MEN1 gene is a tumor suppressor gene in the endocrine tissues that are affected in MEN1. Recent studies have hinted at possibilities to pharmacologically restore the epigenetic changes caused by loss of menin function as therapeutic strategies for MEN1, for example by inhibition of histone demethylases. The current lack of appropriate cellular model systems for MEN1-associated tumors is a limitation for compound testing, which needs to be addressed in the near future. In this review, we look back at the past twenty years of research on menin and the mechanism of disease of MEN1. In addition, we discuss how the current understanding of the molecular function of menin offers future directions to develop novel treatments for MEN1-associated endocrine tumors.

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“…This complex also recruits MLL to promote Th2 cell maturation (Nakata, et al 2010). However, unlike regulation by menin/MLL-mediated H3K4me3 at the promoter (Jin et al 2010) of the target genes, a recent report shows that menin can directly interact with the transactivation domain (TAD) of Myc and then bind to E-boxes to enhance transcription of Myc target genes (Wu, et al 2017). This enhanced transcription of MYC target genes depends on P-TEFb, a key factor to facilitate transcription regulation by MYC (Wu et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…However, unlike regulation by menin/MLL-mediated H3K4me3 at the promoter (Jin et al 2010) of the target genes, a recent report shows that menin can directly interact with the transactivation domain (TAD) of Myc and then bind to E-boxes to enhance transcription of Myc target genes (Wu, et al 2017). This enhanced transcription of MYC target genes depends on P-TEFb, a key factor to facilitate transcription regulation by MYC (Wu et al 2017). The above findings indicate that, by transcriptionally promoting the expression of MYC target genes, menin can stimulate cell proliferation, cellular metabolism and cancer progression in certain types of cancers including MLL fusion protein-induced leukemia cells.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation by the menin pathway

Feng¹,

Ma²,

Hua³

2017

Endocrine-Related Cancer

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There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulating several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt, and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.

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Menin enhances c-Myc-mediated transcription to promote cancer progression

Cited by 42 publications

References 64 publications

Menin regulates the serine biosynthetic pathway in Ewing sarcoma

Menin regulates the serine biosynthetic pathway in Ewing sarcoma

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

Epigenetic regulation by the menin pathway

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