Identification of the key roles of different hexokinases on the diagnosis, prognosis, tumor immunity, drug response: evidence from pan-cancer analysis and construction prognostic HKs signatures

Abstract

Abstract Background Metabolic reprogramming is a key feature of cancer cells and is considered a new hallmark of cancer. With our increasing understanding and appreciation of tumor biology and metabolic complexity, targeting or regulating the expression of certain key metabolic enzymes of metabolic reprogramming may be important strategies for tumor therapy. Glycolysis is an essential part of the complex network of glucose metabolism, and hexokinases (HKs) are the key factors of the glycolysis pathway. Although HKs have also received attention in tumors, their roles in tumors are still not fully and systematically explored, particularly in immunization.Methods Through using multiple online datasets, including the TCGA database, Genecards database, CellMiner database, and Deepscreening database, and combining multiple algorithms, the association of HKs with prognosis, Tumor microenvironment (TME), Tumor immunity, and drug sensitivity were investigated. HKs were also evaluated for their prognostic relevance to specific tumor types and their synergistic effects by constructing prognostic HKs signatures. In particular, the deep learning algorithm predicted the active molecules binding to HKs.Results Cox and survival analysis suggested that HKs were significant factors influencing tumor progression. HKs expression levels strongly correlated with TME, RNAss, and Tumor immunity. Their influences varied in diverse tumors or some specific tumor types. In addition, the relationship between gene expression of HKs and drug sensitivity was investigated, and the results suggested the potential of targeting HKs, especially HKDC1 to improve drug resistance. Furthermore, a validation screen of drug prediction and molecular docking obtained several molecules targeting HKs. Finally, the roles of HKs were confirmed in Brain Lower Grade Glioma (LGG) and Acute Myeloid Leukemia (LAML) by constructing the HKs signatures, further, their homogeneity and heterogeneity were elaborated.Conclusion Our systematic study revealed the significant roles of HKs in tumorigenesis and metastasis, as well as their impact and diverse correlations on tumor immune and metabolic activity. The clinical application of HKs is a viable target and offers the new clinical prospects, especially in the development of personalized medicines for the treatment of LGG and LAML.