Ets-1 p51 and p42 isoforms differentially modulate Stromelysin-1 promoter according to induced DNA bend orientation

The Stromelysin-1 gene promoter contains a palindrome of two Ets-binding sites (EBS) that bind the p51 and p42 isoforms of the human Ets-1-transcription factor. A previous study established that full gene transactivation is associated with a ternary complex consisting of two p51 bound to the two EBS on the promoter. p42, only able to bind one of the two EBS, induces only very weak activity. Here, we investigate the mechanism by which the Stromelysin-1 promoter discriminates between p51 and p42. The differential stoichiometry of the two Ets-1 isoforms arises from the Stromelysin-1 EBS palindrome. The ternary complex requires the presence of two inhibitory domains flanking the DNA-binding domain and the ability to form an intramolecular autoinhibition module. Most importantly, the p51-ternary and the p42-binary complexes induce DNA curvatures with opposite orientations. These results establish that differential DNA bending, via p51 and p42 differential binding, is correlated with the Stromelysin-1 promoter activation process

mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism

Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells

Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation

We thank the Facial Surgery Research Foundation – Saving Faces; Guizhou Department of Education and Guizhou Science and Technology Department

Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers

Cells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, GO, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance

Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers

Cells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, GO, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance

Ets-1 binds cooperatively to the palindromic Ets-binding sites in the p53 promoter.

Due to its autoinhibition for DNA binding, the Ets-1 transcription factor must interact with partners to enhance its affinity for DNA. In a study on the stromelysin-1 promoter, we showed that Ets-1 binds cooperatively to two Ets-binding sites (EBS) organized in palindrome, thereby circumventing the need for a binding partner to counteract autoinhibition. This leads to the formation of an Ets-1-DNA-Ets-1 ternary complex necessary for promoter activation. Here we show that Ets-1 also binds cooperatively to the EBS palindrome of the human p53 promoter, despite the presence of a degenerate EBS to which Ets-1 cannot otherwise bind. Transcriptional transactivation through this palindrome fully correlates to Ets-1 binding. Thus, the cooperative binding model that we initially proposed for the stromelysin-1 promoter may be a general mechanism of Ets-1 binding to palindromic EBS separated by 4bp and a way to counteract binding site degeneracy