Titolo della tesi: Characterization of the mechanisms involved in KCASH oncosuppressors regulation
The Hedgehog (Hh) signaling pathway plays a pivotal role in the morphogenesis
and tumorigenesis of various organs. The aberrant activation of a non-canonical
Hh pathway and the onset of drug-resistant mutations in tumor cells, limit the use
of standard Hh pathway inhibitors in cancer treatment, highlighting the need to
develop new therapeutic strategies.
One of these strategies could be based on the modulation of oncosuppressor
KCASHs proteins. These proteins play an essential role in turning offthe Hh
signalling, by binding Cullin 3 to form a E3 ubiquitin ligase complex which
ubiquitinates and induces the degradation of the histone deacetylase HDAC1,
blocking the activation of the main effector of the Hh pathway, Gli1 We have
studied here the mechanisms of transcriptional regulation of KCASH2, analyzing
the TATA-less KCASH2 proximal promoter and identifying key transcriptional
regulators of this gene: Sp1 and p53. The data obtained suggest that
downregulation of KCASH2 expression in tumors could be mediated by gain of
Sp1 activity and epigenetic silencing events in cells were p53 functionality is lost).
Moreover, to better characterize the modulation mechanism of KASH family we
have searched for new KCASH interactors. In this work, we have demonstrated
that KCTD1 is involved in the regulation of KCASH proteins and in the
modulation of Hh pathway. Indeed, KCTD1 is able to bind both KCASH1 and
KCASH2 proteins and inhibits their degradation, improving their negative effect
on Hh activity., KCTD1 overexpression induces a decrease of HDAC1 protein
levels and an increase of Gli1 acetylation, repressing Gli1 activity. The ability of
KCTD1 to act as a modulator of both KCASH1 and KCASH2, unlike the paralogue
KCTD15, highlights the crucial role of KCTD1 in the negative regulation of the
Hedgehog pathway.
Overall, the data presented in this thesis contribute to the characterization of the
mechanisms modulating the KCASH family of inhibitors of the Hh pathway,
suggesting new potential therapeutic strategies against the Hh dependent tumors.