Περίληψη:
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 gamma-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.
Συγγραφείς:
Papaspyropoulos, Angelos
Angelopoulou, Andriani
Mourkioti,
Ioanna
Polyzou, Aikaterini
Pankova, Daniela
Toskas,
Konstantinos
Lanfredini, Simone
Pantazaki, Anastasia A. and
Lagopati, Nefeli
Kotsinas, Athanassios
Evangelou, Konstantinos
and Chronopoulos, Efstathios
O'Neill, Eric
Gorgoulis, Vassilis
