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means by which the gene is silenced. PRMTs (protein arginine methyltransferases)
modify arginine residues and so epigenetically modify and regulate chromatin struc-
ture and transcriptionally activate or repress the expression of target genes. Promoter
methylation of PDCD4 was reported in breast cancer cell lines some time ago (Wen
et al., 2007) and subsequently in gliomas, where methylation occurred in around half
of tumour issues tested. Methylation corresponded with loss of PDCD4 (Gao et al.,
2009). But Powers et al. (2011) have found that PRMT5, a member of the PRMT
family, methylates a site in the N-terminal region of PDCD4. When co-expressed,
PDCD4 and PRMT5 enhanced breast cancer growth as orthotopic grafts. They sug-
gest that the situation is analogous to a proportion of breast cancers expressing high
PDCD4 have poor prognosis, with high PRMT5 expression functioning as a co-fac-
tor. The role of miRNA-21 in transcriptionally regulating PDCD4 expression was
discussed earlier. Inhibition of miRNA-21 to enhance PDCD4 expression could sup-
press the aggressive behaviour of tumours. Prevention of ubiquitin-mediated degra-
dation of PDCD4 is another potential route. PDCD4 is phosphorylated by both Akt
and p70(S6K) and targeted for ubiquitination and proteasomal degradation (Dorrello
et al., 2006; Schmid et al., 2011). Erioflorin (NSC144151), which inhibits prolifer-
ation of many tumour cell lines, is said to inhibit this process by interacting with
E3-ubiquitin ligase (Blees et al., 2012). So several approaches, conventional as well
as novel, are available to restore PDCD4 suppressor function and prevent its degra-
dation. Some are worthy of further exploration.
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