Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness

Abstract

The highly-conserved NOTCH signaling pathway plays many essential roles in the development of diverse cells, tissues and organs from Drosophila to humans, and dysregulated Notch signaling contributes to several disorders, including vascular and bone defects, as well as several cancers. Here we describe a novel mechanism of NOTCH regulation by reciprocal inhibition of two NOTCH downstream effectors: Deltex1 and HES1. This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH/HES1 signaling. The inhibitory effect of endogenous Deltex1 on NOTCH signaling is mediated through binding with the intracellular domain of NOTCH and ubiquitination and degradation of NOTCH receptors. Conversely, we show that the NOTCH target gene HES1 causes transcriptional inhibition of Deltex1 by directly binding to the promoter of Deltex1. A HES1 binding site is identified 400bp upstream of the transcription start site of Deltex1. HES1-mediated repression of Deltex1 requires the C-terminal H3/H4 and WRPW domains of HES1, which associate with the TLE/Groucho corepressors. Taken together, we define a molecular mechanism regulating NOTCH signaling by reciprocal inhibition of the NOTCH target genes HES1 and Deltex1 in mammalian cells. This mechanism may have important clinical implications for targeting NOTCH signaling in osteosarcoma and other cancers.

The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling

“…Previous results indicated an important role for Hes1 in the development of the interfollicular epidermis (Ambler and Watt, 2007;Moriyama et al, 2008;Rangarajan et al, 2001). A potential explanation for this difference may be that Hes1 expression and function in the epidermis is largely independent of canonical Notch activation, as was shown in other systems (Berechid et al, 2002;Curry et al, 2006;Ingram et al, 2008;Zhang et al, 2010). In partial agreement with this are observations that showed an important role for Hesindependent Notch signaling in epidermal development (Blanpain et al, 2006;Moriyama et al, 2008).…”

Laminar flow downregulates Notch activity to promote lymphatic sprouting

“…We thus searched for putative modifiers that were differentially expressed in LECs and BECs under the laminar flow conditions. DTX1 and DTX3L were identified from our transcriptional profiling analyses as the candidates based on their previous association with Notch signaling as a heterodimeric E3 ligase (39)(40)(41)(42). While DTX3L mRNA was upregulated specifically in LECs in response to laminar flow, DTX1 mRNA was commonly upregulated in LECs and BECs ( Figure 6, A and B).…”

Hes1: a key role in stemness, metastasis and multidrug resistance

“…The results suggest that Hes1 represses Deltex1 which can block osteosarcoma invasiveness by binding to the Deltex1 promoter. 39 There is yet another mechanism by which Hes1 is able to promote tumor metastasis. Hes1 has been implicated in a tumor cell "osteoblast-like" phenotype and tumor bone metastasis.…”