Linc00173/YB1 Axis Mediates Small Cell Lung Cancer Chemoresistance By Reprogramming Glucose Metabolism

Small cell lung cancer(SCLC)is an aggressive malignancy with a 5-year overall survival rate of approximately 5%.The traditional first line treatment is etoposide(VP16)/irinotecan plus cisplatin(CDDP).Most patients initially respond well to the chemotherapy but unavoidably develop resistance as disease progress.Therefore,there is an urgent need for more detailed understanding of the molecular mechanisms involved in SCLC chemoresistance,which will promote the development of new therapies.Long noncoding RNAs(lncRNAs)are a large group of RNA molecules greater than 200nt in length with limited or no protein-coding capacity.Emerging evidence suggests that LncRNAs play tremendous roles in tumorigenesis possibly altered metabolism.However,the roles that LncRNAs play in SCLC and the specific mechanisms are still poorly understood.Aerobic glycolysis,also termed "the Warburg effect",is recently recognized as one of the hallmarks of cancer cells.Lots of tumor cells display activation of glycolysis,producing energy mainly through glycolysis even in the presence of Oxygen.Although it is a less efficient way,compared to mitochondrial oxidative phosphorylation(OXPHOS),in energy production,aerobic glycolysis increases biosynthesis to promote the growth of cancer cells under difficult conditions.Several studies have showed that high rate of aerobic glycolysis is associated with tumorigenesis,progression and drug resistance.Key enzymes of glucose metabolism have also been reported to be aberrantly expressed in cancers.Accordingly,drugs that can disturb glucose metabolism reprogramming of tumor cells may exhibit potential therapeutic effects in clinical treatment of cancers.However,the role of glucose metabolism in SCLC chemoresistance remains unknown.Consequently,inhibition of the Warburg effect may open a feasible window for SCLC treatment.Our prior research demonstrated that Linc00173 might function as an oncogene in SCLC,promoting cancer cell progression and chemoresistance not only in cultured cells,but also animal models and human tissues.Here,we uncovered that Linc00 173 is involved in SCLC chemoresistance through reprogramming glucose metabolism.We performed RNA pull-down assays followed by a mass spectrometric analysis and find out YB1 is one of the RNA binding proteins of Linc00173.RIP sequencing and bioinformatics analysis showed that YB1 is largely associated with glucose metabolism and two key enzymes of glycolysis and the pentose phosphate pathway(PPP),hexokinase(HK2)and glucose-6-phosphate dehydrogenase(G6PD),may be potential downstream genes of Linc00173/YB1.During the process,Linc00173 directly binds to and phosphorylates YB1 protein,elevates the expression of HK2 and G6PD,which leads to increasing glycolysis and PPP flux.Furthermore,we demonstrated that Linc00173-mediated activation of HK2 and G6PD is pivotal for SCLC chemoresistance.In addition,we found that 3-BrPA and RRx-001,the inhibitors of HK2 and G6PD,exhibit a synergistic anti-tumor effect with chemotherapy in animal experiments including a PDX model,suggesting that these key enzymes of glycolysis and PPP could potentially be new therapeutic targets for SCLC treatment.Taken together,we revealed the mechanism of Linc00173 interacts with YB1 and increases SCLC chemoresistance through the glucose metabolism reprogramming,indicating that Linc00173-YB1-G6PD/HK2 axis may be a potential therapeutic target in SCLC.