Title : Protein structure maintenance, intracellular signaling and tumor suppression contributed by zinc finger protein ZMYND10
Abstract:
On short arm of human chromosome 3, a region 3p21, which is deleted in a variety of tumors, harbors a cluster of putative tumor suppressor genes (TSGs). One of the TSG candidates, BLU, coding for a zinc protein ZMYND10 has initially recognized as a fragment lost in lung cancers. ZMYND10 has also been reported to be a structural protein whose mutation is responsible for pathogenesis of primary ciliary deficiency (PCD), and data suggests that ZMYND10 plays a role in maintenance of protein structure by serving as a co-chaperone through interacting with heat shock protein 90 (HSP90) and FK 506 binding proteins (FKBPs) like FKBP8. Some members of FKBP family has been shown to modulate the activity of NFkappaB pathway by phosphorylation modifying the regulating kinase. In addition to be classified as a member of zinc finger myeloid Nervy deformed autoregulatory containing (ZMYND) known as ZMYND10, it is also classified as a member of the dynein assembly associated factor (DNAAF), termed DNAAF7. Members of this family of DNAAF have been identified as cancer related with differentially expressed in malignancy as compared with normal controls. At transcript level, the silence of BLU due to hypermethylation on upstream promoter region has been noted in NPC, glioma, hepatocellular carcinoma (HCC) and other cancers. We reported that re-expression of BLU reduced the level of IKKalpha and hence the level of p65/NFkappaB3 to downregulate apoptotic inhibitors CFLAR and cIAP to potentiate TRAIL induced apoptosis. It has also been shown that ZMYND10 inhibits signalling of JNK and ERK of mitotic activated protein kinase (MAPK) family to inhibit colony formation and arrest cell cycle. ZMYND proteins have been known to modify histone marks by regulation of histone methylation. We observed that ZMYND10 downregulates Enhancer of zeste homolog 2 (EZH2), alternatively termed KMT6A to block bi- or trimethylase of a repressive mark lysine 27 on histone 3 (H3K27) to remove the transcription repression on an inhibitor of cell cycle progression p16/CDKN2A. The effects of ZMYND10 on NFkappaB pathway and histone modification remain to be mechanistic validation. Data obtained from public bioinformatics databases also reveals that ZMYND10 is downregulated in several human tumors, notably lung squamous cell cancer (LUSC) and adenocarcinoma (LUAD), renal clear cell and papillary cell carcinoma (KIRC and KIRP), breast cancer (BRCA)? cervical squamous cell carcinoma (CESC) and several other cancers. To match with the downregulated expression registered in databases TIMER2 and GEPIA (Gene Expression Profiling Interactive Analysis), overall (OS) and relapse free (RFS) survival in early or late stage LUAD, LUSC, KIRC and KIRP and BRCA were correlated with the reduced level of ZMYND10. The observation remains to be expanded with more clinical specimens of more diversified background, so as to establish ZMYND and DNAAF proteins as antitumor therapeutic targets.
