SIRT1 is a class III histone

SIRT1 is a class III histone Fluoro Sorafenib deacetylase capable of dea cetylating lysine residues on nuclear proteins, which is thought to affect their stability, transcriptional activity, and translocation. Recently, SIRT1 mediated deacetyla tion of nuclear proteins such as p53, FO O, and Ku70, has been reported to promote cell survival. Roles for SIRT1 in skin, colon, breast, and lung cancers have been demonstrated through its affects on one or more of the aforementioned nuclear proteins. Additionally, SIRT1 can regulate vascular endothelial homeostasis by controlling angiogenesis and vascular function, and also regulates the transcription of numerous genes by interacting with transcription fac tors. For e ample, upon recruitment to chromatin by transcription factors, SIRT1 deacetylates histones to suppress gene transcription.

Despite evidence for SIRT1 involvement in a variety of cell regulatory and physiological processes, the role of SIRT1 in regulating oral cancer metastasis and EMT remains enigmatic. In this study, we investigated the involvement of SIRT1 in EMT as it occurs in oral cancer metastasis. We found that SIRT1 e pression was substantially downregulated in OSCC cell lines, and was also widely attenuated in OSCC tumors as compared with e pression in paired normal tissues. SIRT1 overe pression repressed the EMT process in oral cancers and blocked migration of OSCC cells in vitro. In contrast, knockdown of SIRT1 in oral cancer cells enhanced EMT and cancer metastasis in vitro. We also show that SIRT1 regulates e pression of the epithelial marker E cadherin, as well as the mesenchymal markers vimentin and N cadherin.

Moreover, we found that SIRT1 targets Smad4 to reduce EMT and MMP7 e pression. Finally, we show that SIRT1 overe pression reduced the invasiveness and metastasis of oral cancer cells in im munodeficient mice. In summary, our data show that SIRT1 inhibited the EMT process in oral cancer by dea cetylating Smad4 and repressing e pression of MMP7. These results suggest a role for SIRT1 as a metastasis suppressor in oral cancer. Results Variable levels of SIRT1 e pression and its activity To evaluate the role of SIRT1 in regulating oral cancer metastasis and EMT, we first investigated whether SIRT1 e pression in normal primary human oral keratinocytes differed from that in OSCC cells.

We e amined the SIRT1 mRNA and protein levels in 5 OSCC cell lines and compared them with their levels in HOK cells. We found that both the transcription and translation products of SIRT1 were more highly e pressed in HOKs compared to their e pressions in various OSCC cell lines. Ne t, we iso lated the nuclear fractions Entinostat of HOK cells and OSCC cells, immunoprecipitated the endogenous SIRT1, and tested for its deacetylase activity. Surprisingly, we found that all OSCC cell lines had drastically lower levels of SIRT1 activity compared with those in HOK cells.

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