Recent studies showed that the increased expression of Auror
Recent studies showed that the increased expression of Aurora B kinase directly proportional to the tumor invasion and metastasis . The Aurora B kinase regulates the PI2K/Akt signaling pathway has a significant role in tumor invasion and metastasis that leads to phosphorylation of GSK3β on ser 9 residues and inhibits the kinase activity . This ultimately induces the activation of Wnt signaling downstream target genes by nuclear translocation of β-catenin. Hence, by the inhibition of Aurora B kinase, suppress PI3K/Akt signaling pathway that eventually inhibits the metastasis and tumor invasion . Without β-catenin mutation, this Aurora B kinase overexpressed in many cancers when it gets interacts with axin . This inhibits the activity of the destruction complex leads to nuclear translocation of β-catenin again and activating the downstream target genes .
SIRT1 The human SIRT1 contains 747 AZD 5153 and consists of 4 regions; the N-terminal (nuclear localization signal, 41–46 aa), allosteric side (183–243), the conserved catalytic domain (deacetylation at the center domain) and the C-terminal region (631-365 aa) . The nuclear reading and exporting sequence of the N-terminal region are essential to allow SIRT1 to translate freely between nucleus and cytoplasm . There are two proteins actively involved to regulate SIRT1 activity through positive and negative cellular stress response. Especially, the N-terminal catalytic core compacted with allosteric domain, positively regulate the SIRT1 activity . The active regulator of SIRT1 (AROS) is the direct regulator of SIRT1, which significantly enhanced the deacetylation of SIRT1, inhibits p53 degradation during a DNA damage condition . Conversely, the recent identification of negative regulator for SIRT1 is DBC-1 (deleted breast cancer-1). It binds to the catalytic domain of SIRT1, a block to the substrate binding to SIRT1 to inhibit it is activity and function. By the inhibition and reduction of DBC-1 can enhance SIRT1 mediated p53 deacetylation in order to inhibit the apoptosis during double stranded DNA breaks . However, the SIRT1 activity is also regulated by cis-elements of it is own peptide. On the other hand, the SIRT1 C-terminal can interact with it is catalytic core domain by competing with DBC1 to activate SIRT1. SIRT1 plays an important role in cellular processes such as chromatin structure, gene transcription, circadian rhythm, inflammation and metabolism . The histone protein acetylation/deacetylation can determine the chromatin for gene transcription. SIRT1 mediated deacetylates H1K26, H3K9 and H4K16 can facilitate the chromatin DNA compaction to silence the gene expression . Whereas, the non-histone substrates of SIRT1 are also control metabolism, gene transcription and signal transduction.
Interaction of SIRT1 and aurora kinases The previous findings suggested that the inhibition of HDAC especially SIRT1 activate proteosomal mediated degradation of both Aurora A and B kinases . This is following the interaction of heat shock protein (Hsp70) with Aurora A kinase and degrades it . On the other hand, the HDAC3 complex with A kinase-Anchoring proteins (AKAP95)/HA95 deacetylates histone 3 to provide hypoacetylated H3 tail, a preferred substrate for Aurora B kinase . Hence, these findings suggest that the Aurora B kinase protein is one of the targets for HDAC mediated G2/M arrest . Therefore the combination of Aurora inhibitors and SIRT1 HDAC inhibitors are highly effective against cancer cell lines .
Interaction of SIRT1 and Wnt Signaling Pathway Remarkably, the dishevelled protein in Wnt Signaling pathway has been regulated by the class III histone deacetylase of SIRT1, where it binds to the frizzled receptor . As there are many genes involved in the activation of Wnt signaling pathway includes Wnt1, Wnt3a, Wnt5a, Wnt11 and Wnt16 . In this series, NAD-dependent deacetylase SIRT1 plays an activator of Wnt signaling pathway, regulate numerous physiological processes include metabolism, aging, neurodegeneration, heart disease and cancer in mammals . It also has ability to catalyze deacetylation of DNA core histone on its lysine residue in nucleosome . Several reports indicate that the interaction between SIRT1 and regulation of Wnt signaling pathway component act as a tumor promoter . Ultimately, this gets interacts with all the Wnt components, described as follows