The Essence of the Hippo Signalling System - Therapeutic Strategies in Cancer Biology and Pathology - page 139

Upstream Regulators of Hippo Are Tumour Suppressors
Suppressor Function of Atypical Cadherins Dachsous and Fats
Hippo signalling is modulated by many upstream elements which have themselves
been attributed with tumour suppressor function. Prominent among them are the
atypical cadherins, Fats and Dachsous (Dachs). The Fats seem to act downstream of
Dachs. Dach1 gene encodes a chromatin associated protein that binds to transcrip-
tion factors and regulates gene expression. Dach1 contains the highly conserved ski
domain. Dach1 is said to regulate the Six family genes involved in organogenesis
and also implicated in the control of cell proliferation and cell motility in embry-
onic development. It probably acts as a co-repressor of Six6 to regulate cell pro-
liferation via repression of cyclin-dependent kinase inhibitors. Interestingly it is
also believed to inhibit TGF-β signalling by interacting with Smad4 receptor and
NCOR1 (see UniProtKB/Swiss-Prot: DACH1_HUMAN, Q9UI36). In essence, the
Fat/Dachs/Hippo axis is closely associated with these biological features, essential
in tumour development, invasion and secondary spread. In murine mammary epithe-
lial cells, loss or suppression of Fat4 expression by promoter methylation promoted
tumorigenesis, whilst induced re-expression inhibited tumorigenesis. In human
breast cancer cell lines and tissues, loss of Fat4 was encountered. Loss of expres-
sion by methylation was found in 3/6 established breast cell lines and 3/5 primary
breast cancers (Qi et al., 2009). Although this is a limited exercise with reference to
human breast cancer, Qi et al. (2009) did go on to show that the loss of Fat4 led to
overexpression of YAP, thus linking the loss of Fat4 unequivocally with Hippo sig-
nalling. Katoh and Katoh (2006) have claimed that in silico analysis Fats 1-4 were
differentially expressed in various human neoplasms as well as in normal tissues.
How significant Fat signalling is in terms of relevance to tumorigenesis is difficult
to determine at present, especially since mutation or deletions of Fat4 are somewhat
infrequent (approximately 5%) in gastric tumours as compared with p53 (>70%) for
instance (Zang et al., 2012). But we do not know what the status is in breast or other
cancers. Genetic prolife of Fat apart, when read in the context of the demonstration
that Dachsous can function independently of Fat, Fat deregulation may not seem
always relevant for tumorigenesis (Matakatsu and Blair, 2006).
NF2/Merlin as Tumour Suppressor
NF2/Merlin and Drosophila melanogaster protein called Expanded are ERM-
related cytoskeletal proteins. Merlin has been shown to possess a significant abil-
ity of tumour suppression besides its ability to regulate the size of organs. FRMD6
(Willin) is seen as the human homologue of Expanded. Loss of FRMD6 has been
reported to produce cellular phenotypic features reminiscent of EMT (Angus et al.,
2012). The suppressor effects of the human homologue were seen in breast cancer
cell lines where overexpression seemed to have led to the inhibition of cell prolifera-
tion colony formation, soft agar colony growth in vitro and in vivo tumour growth
in nude mice. However, these effects occurred independently of Hippo signalling