| Autor: |
Papaspyropoulos, Angelos, Angelopoulou, Andriani, Mourkioti, Ioanna, Polyzou, Aikaterini, Pankova, Daniela, Toskas, Konstantinos, Lanfredini, Simone, Pantazaki, Anastasia A, Lagopati, Nefeli, Kotsinas, Athanassios, Evangelou, Konstantinos, Chronopoulos, Efstathios, O'Neill, Eric, Gorgoulis, Vassilis |
| Zdroj: |
EMBO Reports; 2/3/2022, Vol. 23 Issue 2, p1-13, 13p |
| Abstrakt: |
RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A‐dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH‐HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO‐targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A‐depleted environment renders cells non‐responsive to the downstream effects of γ‐secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors. Synopsis: The RASSF1A tumor suppressor uncouples the NOTCH‐HES1 axis by triggering SNURF/RNF4‐mediated HES1 ubiquitination. Loss of RASSF1A promotes cancer stemness via NOTCH‐independent HES1 stabilization and confers resistance to γ‐secretase inhibitors. A RASSF1A/RNF4/HES1 protein complex is responsible for RNF4‐mediated HES1 degradation in cancer cells.RASSF1A promotes cancer stemness through HES1‐dependent activation of the core pluripotency network.RASSF1A expression inversely correlates with HES1 levels across the vast majority of human tumour types.HES1 stabilization in a RASSF1A‐depleted environment renders cancer cells non‐responsive to γ‐secretase inhibitors. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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