STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

Abstract

STAT3 and HIF1α are two fundamental transcription factors involved in many merging processes, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remain unclear. In mouse embryonic stem cells (ESCs) we manage to determine the specific subset of hypoxia-induced genes that need STAT3 to be properly transcribed and, among them, fundamental genes like Vegfa, Hk1, Hk2, Pfkp and Hilpda are worth mentioning. Unexpectedly, we also demonstrated that the absence of STAT3 does not affect the expression of Hif1α mRNA nor the stabilization of HIF1α protein, but the STAT3-driven regulation of the hypoxia-dependent subset of gene could rely on the physical interaction between STAT3 and HIF1α. To further elucidate the physiological roles of this STAT3 non-canonical nuclear activity, we used a CRISPR/Cas9 zebrafish stat3 knock-out line. Notably, hypoxia-related fluorescence of the hypoxia zebrafish reporter line (HRE:mCherry) cannot be induced when Stat3 is not active and, while Stat3 Y705 phosphorylation seems to have a pivotal role in this process, S727 does not affect the Stat3-dependent hypoxia response. Hypoxia is fundamental for vascularization, angiogenesis and immune cells mobilization; all processes that, surprisingly, cannot be induced by low oxygen levels when Stat3 is genetically ablated. All in all, here we report the specific STAT3/HIF1α-dependent subset of genes in vitro and, for the first time with an in vivo model, we determined some of the physiological roles of STAT3-hypoxia crosstalk.

ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis

“…Meanwhile, STAT5 has been reported to play an important role in tumor progression and the activation of the glycolytic pathway ( 62 ). Further, a study indicates that STAT3 enhances the transcription of HK2 to modulate physiological responses under hypoxia ( 63 ), where HK2 is a crucial enzyme in the glycolytic pathway. Our study identified the role of STAT1 in the enhanced transcriptional regulation of ENO2, further elucidating the energy metabolism mechanism during hypoxia or anoikis resistance in tumors, presenting a potential target for future therapies in ATC.…”

A positive feedback loop between PFKP and c-Myc drives head and neck squamous cell carcinoma progression

“…PFKP is also subject to regulation by HIF-1α at the translational level, promoting cancer cell invasion [ 59 ]. Moreover, other transcription factors, such as Snail and STAT3, have been reported to participate in the transcription regulation of PFKP in various types of cells [ 60 , 61 ]. PFKP may also undergo post-transcriptional regulation by the RNA-binding protein fat mass and obesity-associated protein (FTO) [ 44 ].…”

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…The targets of studies include lysosomes [ 170 , 171 ], endoplasmic reticulum [ 172 ], membranes [ 173 ], membrane channels [ 174 ], cytoskeleton [ 175 ], recombination processes [ 176 ], aneuploidy [ 177 ], expression regulation [ 178 ], and signaling [ 179 ]. There is research on the genetic basis of the organism’s response to oxidative stress [ 180 , 181 , 182 , 183 , 184 ], hypoxia [ 185 , 186 , 187 ], sodium ion uptake from the surrounding aquatic environment and ammonia excretion [ 188 , 189 , 190 ], inflammation processes [ 191 , 192 ], immunity [ 193 , 194 , 195 , 196 ] and disease resistance [ 197 , 198 , 199 , 200 , 201 ].…”