Notch3 Functions as a Tumor Suppressor by Controlling Cellular Senescence

Abstract

Notch signaling regulates a broad spectrum of cell fate decisions and differentiation. Both oncogenic and tumor suppressor functions have been demonstrated for Notch signaling. However, little is known about the underlying mechanisms of its tumor suppressor function. Here we report that expression of Notch3, a member of Notch family transmembrane receptors, was elevated in human cells during senescence activated by various senescence-inducing stimuli. This up-regulation of Notch3 was required for the induction of p21 expression in senescent cells. Down-regulation of Notch3 led to a delayed onset of senescence and extended replicative lifespan, whereas adventitious expression of Notch3 was sufficient to activate senescence and p21 expression. The ability of Notch3 to induce senescence and p21 expression was dependent on the canonical Notch singling. Deletion of p21 in cells significantly attenuated Notch3-induced senescence. Furthermore, a significant decrease in Notch3 expression was observed in human tumor cell lines as well as primary human breast cancer and melanoma samples compared to normal tissues. Restoration of Notch3 expression in human tumor cells resulted in inhibition of cell proliferation and activation of senescence. Collectively, our results reveal a novel function of Notch3 in senescence regulation and tumor suppression.

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

“…However, our findings and other recent reports have begun to reveal novel signaling effects and preferential targets for NOTCH3 (Baeten and Lilly, 2015;Cui et al, 2013;Wang et al, 2016). As it stands, NOTCH3 appears to be unique among the receptors.…”

Notch signaling molecules as prognostic biomarkers for non-small cell lung cancer

“…Different Notch receptors play different, even opposing, roles in tumor development, showing the complexity of Notch signaling in cancer. The expression of Notch 3 has been found to be significantly decreased in human tumor cell lines, and in primary human breast cancer and melanoma samples compared with normal control tissues (21).…”

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

“…64,65 However, sustained activation of Notch-p21 contributes to an irreversible senescent phenotype. 8,66 In contrast, cells that express full-length Hes1 genes resume proliferation, after a p21-induced senescent phenotype, as Hes1 transcriptionally represses p21 in a bHLH domain-dependent manner and Hes1 keeps quiescent cells from the differentiation state mentioned previously. 8,67 Based on this, we may conclude that the quiescence-based dormancy relies on the balance between Hes1 and p21.…”