SIRT1 and HIF-1 are both highly conserved and constitutively expr

SIRT1 and HIF-1 are both highly conserved and constitutively expressed proteins that are positive factors needed to resolve Carfilzomib Phase 2 metabolic and oxidative stress. In addition, both are required for normal tissue development [62] and are both targets for post-transcriptional regulation by the microRNA, miR-119a-5p [51]. Therefore, as suggested by our findings, it seems plausible that their interaction should facilitate, not hinder each other’s function for normal tissue homeostasis. Although SIRT1 and HIF-1 are vital for the maintenance of healthy tissue, their expression may also have undesirable consequences in a malignant environment. Our observation that SIRT1 is highly expressed in HCC cell lines is consistent with that of others who reported that SIRT1 is overexpressed in liver, colon, breast, and prostate cancers and squamous cell carcinomas [63], [64].

Cancer cells have the ability to hijack cellular processes that can promote their survival under harsh conditions that exist in a tumor microenvironment. SIRT1 overexpression could provide tumor cells a survival advantage. Transient overexpression of SIRT1 was shown to be sufficient to stimulate basal rates of autophagy, which is used by cancer cells to help them survive under stressful tumor microenvironment conditions [65]. In this context, the inhibition of SIRT1 is becoming a novel approach for the development of new treatment strategies for some cancers. However, many of the available sirtuin inhibitors have limited potency and isoform specificity.

This has prompted the development of novel inhibitors that can distinguish between sirtuin family members to better target the desired effector function [66]. Studies reporting that sirtuins can influence the activity and function of HIF transcription factors are of high interest, since HIF proteins are also frequently overexpressed in cancers, are driving force in many steps of cancer progression and are a negative predictors for patient outcome (reviewed in [67]). As suggested by our data, an additional benefit of targeting SIRT1 would be the inhibition of HIF-1 activity. However, as introduced earlier, SIRT1 targets the activity of many other transcription factors and co-activators. An undesirable effect of inhibiting SIRT1 activity could be obtained if, for example, NF-��B is constitutively activated in the targeted cancer cells.

SIRT1 suppresses NF-��B signaling [24], [68] and release of this suppression could stimulate cancer cell proliferation, inhibit apoptosis and increase angiogenesis and metastasis [69]. Interestingly, SIRT1 is not the only sirtuin Cilengitide family member shown to regulate HIF-1 function. SIRT6 expression interferes with HIF-1-mediated transcriptional activity by interfering at the promoter of target genes [38]. SIRT3, a mitochondrial deacetylase functions as a tumor suppressor protein by its ability to inhibit the generation of reactive oxygen species (ROS) [70].

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