Molecular descriptions of thyroid lines were matched to the originating tumors, setting a new standard for cell line characterization. Furthermore, suppressed RhoB is implicated as a molecular target for therapy against ATC because five classes of drugs up-regulate RhoB and inhibit growth dose-responsively.
BackgroundEpithelial-to-mesenchymal transition (EMT) results in changes that promote de-differentiation, migration, and invasion in non-small cell lung cancer (NSCLC). While it is recognized that EMT promotes altered energy utilization, identification of metabolic pathways that link EMT with cancer progression is needed. Work presented here indicates that mesenchymal NSCLC upregulates glutamine-fructose-6-phosphate transaminase 2 (GFPT2). GFPT2 is the rate-limiting enzyme in the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the obligate activator of O-linked N-acetylglucosamine transferase (OGT).MethodsAnalysis of our transcriptomic data indicates that GFPT2 is one of the most significantly upregulated metabolic genes in mesenchymal NSCLC. Ectopic GFPT2 expression, as well as gene silencing strategies were used to determine the importance of this metabolic enzyme in regulating EMT-driven processes of cell motility and invasion.ResultsOur work demonstrates that GFPT2 is transcriptionally upregulated by NF-κB and repressed by the NAD+-dependent deacetylase SIRT6. Depletion of GFPT2 expression in NSCLC highlights its importance in regulating cell migration and invasion during EMT.ConclusionsConsistent with GFPT2 promoting cancer progression, we find that elevated GFPT2 expression correlates with poor clinical outcome in NSCLC. Modulation of GFPT2 activity offers a potentially important therapeutic target to combat NSCLC disease progression. Electronic supplementary materialThe online version of this article (10.1186/s12964-019-0335-5) contains supplementary material, which is available to authorized users.
Lung cancer is one of the three most common cancers among men and women and causes more cancer-related deaths than any other type of carcinoma. Of the two subtypes, Non-small cell lung cancer (NSCLC) is the most common 1-3 . These tumors are characteristically high grade, PET-positive, indicating heightened glucose uptake and altered cancer metabolism. Sirtuin 6 (SIRT6) is a member of the sirtuin family of histone deacetylases and has previously been shown to be a key regulator of glucose metabolism, DNA damage repair, and aging [4][5][6][7] . SIRT6 has been demonstrated to act as a tumor suppressor in colon, pancreatic and liver cancer 4,8 .However, its role in NSCLC remains elusive. Here, we have developed a mouse model to study the role of SIRT6 in NSCLC, utilizing a KRAS G12D driver mutation and p53 flox/flox to drive lung tumorigenesis in response to intranasal deliver of adenovirus expressing Cre recombinase. Work described here indicates that SIRT6 expression is necessary for lung tumor initiation and progression. Loss of SIRT6 expression resulted in a delay of tumor growth leading to decreased tumor burden and prolonged survival compared to animals expressing both wild-type alleles of SIRT6. Utilizing NSCLC developed mouse cell lines, we were able to show that cells lacking SIRT6 exhibited decreased proliferation, decreased formation of colonies of soft agar and increased senescence, providing a possible mechanism for the delay in tumor initiation and formation in vivo. Since NSCLC maintain SIRT6 mRNA expression in primary tumors, we sought to identify a potential mechanism by which cancer cells post-translationally regulate SIRT6 activity. In this study, we propose a mechanism where by SIRT6 can be lost in response to the metabolic state ii of the cell. Data presented here shows that SIRT6 undergoes a glucose-responsive N-terminal cleavage that is predicted to result in loss of its chromatin-localization sequence (CLS), causing it to dissociate from chromatin. More specifically, we found that SIRT6 is directly O-GlcNAcylated and that the O-GlcNAc transferase (OGT) is necessary for this cleavage to occur. Our lab has previously shown that OGT also OGlcNAcylates the NF-κB subunit, p65, to allow for its full transcriptional activation.As SIRT6 and NF-κB have been previously shown to physically interact and antagonize one another in transcription of key metabolic genes, loss of the CLS of SIRT6 and transcriptional activation of p65 in response to O-GlcNAcylation may serve as a mechanism for p65-induced transcription of metabolic target genes 9 .Work described in this thesis underscores the importance of SIRT6 as an essential enzyme required for NSCLC development, yet once carcinoma is established it becomes dynamically misregulated by altered metabolic flux of the cancer cell.iii ACKNOWLEDGEMENTS
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