Biology Reference
In-Depth Information
20
EPB41L3 and CADM1 Tumour
Suppressor Function
The membrane proteins EPB41L3 (erythrocyte membrane protein band 4.1-like
3 also known as DAL-1 and 4.1B) and CADM1 have been focused upon in recent
years. They occur as a complex and have been implicated in intercellular adhesion.
EPB41L3 belongs to the family of proteins possessing N-terminal FERM (F for 4.1
ERM) domain. ERM proteins have a C-terminal F-actin binding region (Chishti
et al., 1998; Pearson et al., 2000). The FERM domain proteins including EPB41L3
in this way link cytoskeletal proteins and the cell membrane.
Both EPB41L3 and CADM1 proteins are downregulated in cancers. Both have
been linked with breast cancer invasion and progression (Takahashi et  al., 2012).
Repression of its expression has shown correlation with progression of NSCLC
where its methylation has shown tumour stage-dependent increase (Kikuchi et  al.,
2005). Enforced expression of EPB41L3 in A549 suppressed cell migration, whilst
suppressing the endogenous protein enhanced migration (Zhang et al., 2012d). These
authors have portrayed its expression as related to metastasis for 5/7 established
NSCLC cell lines showed no expression. Cells harvested from pleural fluid showed
no expression of the protein. Nonetheless, it is disconcerting to note the somewhat
promiscuous use of the term metastatic in cancer literature.
Dafou et al. (2010) approached this problem by transferring chromosome 18 into
the ovarian cancer cell line TOV21G. This led to suppression of tumorigenesis. They
identified several genes located on chromosome 18 in the hybrid cell line TOV21G.
Whilst EPB41L3 was expressed in normal ovarian epithelial cell lines, it was meth-
ylated and suppressed in a majority of ovarian cancer cell lines. Methylation of the
gene was also found in ovarian cancer tissue. Although these findings are interest-
ing per se , one cannot fail to notice that among other genes that were overexpressed
in the hybrid TOV21G cells is cadherin. Taking a quizzical view, it seems surpris-
ing that a near 17-fold increase in its expression would certainly have contributed to
the suppression of tumorigenesis and alterations of in vitro cell motility. EPB41L3
is a cytoskeletal protein involved with the actin cytoskeleton and with intercellular
adhesion phenomenon. So the transfection studies should also have included cad-
herin transfer. As the authors themselves have pointed out EPB41L3 is hypermeth-
ylated in many human cancers and possible co-ordinated functioning of EPB41L3
with cadherin cannot be excluded. Furthermore, EPB41L3 similarly co-operates
with another membrane component CADM1 in the cell-cell adhesion process.
CADM1 is said to interact with the actin cytoskeleton through the mediation of
EPB41L3 (Yageta et al., 2002). It may be noted in this context that hypermethyla-
tion and silencing of EPB41L3 occurs in Nasal NK/T-cell lymphoma (NL) correlated
with concomitant methylation of the CADM1 gene (Fu et al., 2009). CADM1 is an
 
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