Chromatin, Gene, and RNA Regulation Menin Directly Represses Gli1 Expression Independent of Canonical Hedgehog Signaling

نویسندگان

  • Buddha Gurung
  • Zijie Feng
  • Xianxin Hua
چکیده

Multiple endocrine neoplasia type 1 (MEN-1), is a familial tumor syndrome resulting from mutations in the tumor suppressor gene menin (MEN1). Menin plays an essential role in both repressing and activating gene expression. However, it is not well understood how menin represses expression of multiple genes. Upon MEN1 excision, the transcription factor Gli1 and its target genes, including Ptch1 and c-Myc, were shown to be elevated in the absence of an apparentHedgehog) pathway-activating ligand orwhen Smoothened (SMO), a key component of the pathway, is inhibited. Menin binds to the GLI1 promoter and recruits PRMT5, a histone arginine methyltransferase associated with transcriptional repression. Both PRMT5 binding and histone H4 arginine 3 methylation (H4R3m2s) are decreased at the GLI1 promoter in MEN1-excised cells. Moreover, MEN1 ablation resulted in increased binding of transcriptionally active Gli1 at the GLI1 promoter in a manner not influenced by the canonical Hedgehog signaling pathway. Inhibition of Gli1 by the small-molecule inhibitor GANT-61 led to decreased expression of Gli1 and its target genes in MEN1-depeleted cells. Furthermore, GANT-61 potently suppressed proliferation of MEN1-excised cells as compared with control cells. These findings uncover a novel epigenetic linkwherebymenin directly repressesGli1 expression, independent of the canonicalHedgehog signaling pathway, via PRMT5 and its repressive H4R3m2s mark. Implications: Inhibition of GLI1 suppresses neuroendocrine tumors harboring mutations in theMEN1 gene.Mol Cancer Res; 11(10); 1215–22. 2013 AACR.

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Menin directly represses Gli1 expression independent of canonical Hedgehog signaling.

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تاریخ انتشار 2013