The role of the HIF‐1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer

Abstract

Background: As a rate-limiting enzyme of glycolysis, pyruvate kinase muscle isozyme M2 (PKM2) participates in tumor metabolism and growth. The regulatory network of PKM2 in cancer is complex and has not been fully studied in bladder cancer. The 5-methylcytidine (m5C) modification in PKM2 mRNA might participate in the pathogenesis of bladder cancer and need to be further clarified. This study aimed to investigate the biological function and regulatory mechanism of PKM2 in bladder cancer. Methods:The expression of PKM2 and Aly/REF export factor (ALYREF) was measured by Western blotting, qRT-PCR, and immunohistochemistry. The bioprocesses of bladder cancer cells were demonstrated by a series of experiments in vitro and in vivo. RNA immunoprecipitation, RNA-sequencing, and dualluciferase reporter assays were conducted to explore the potential regulatory mechanisms of PKM2 in bladder cancer. Results:In bladder cancer, we first demonstrated that ALYREF stabilized PKM2 mRNA and bound to its m5C sites in 3′-untranslated regions. Overexpression of ALYREF promoted bladder cancer cell proliferation by PKM2-mediated glycolysis. Furthermore, high expression of PKM2 and ALYREF predicted poor survival in bladder cancer patients. Finally, we found that hypoxia-inducible factor-1alpha (HIF-1α) indirectly up-regulated the expression of PKM2 by activating ALYREF in addition to activating its transcription directly. Conclusions:The m5C modification in PKM2 mRNA in the HIF-1α/ALYREF/PKM2 axis may promote the glucose metabolism of bladder cancer, providing a new promising therapeutic target for bladder cancer.

A Prognostic Risk Score Based on Hypoxia-, Immunity-, and Epithelialto-Mesenchymal Transition-Related Genes for the Prognosis and Immunotherapy Response of Lung Adenocarcinoma

“…And RNA methylation highly interconnected with hypoxia, immune response and EMT( Lin et al, 2019 ; Chao et al, 2020 ; Wang E. et al, 2021 ). In previous study, researcher identified hypoxia can induced the sumolytion of m 6 A enzyme( Hou et al, 2021 ), hypoxia-inducible factor-1 alpha (HIF-1α) can drive m 5 C modification to promote tumorigenesis( Wang J. Z. et al, 2021 ), m 1 A and m 6 A modification can significantly affect the infiltration of immune cells( Cai et al, 2021 ; Gao et al, 2021 ), m 7 G modification can drives immune evasion ( Devarkar et al, 2016 ), and m 6 A, m 7 G modification can induce EMT in cancer development ( Yu X. et al, 2020 ; Xia et al, 2021 ).…”

5-Methylcytosine Related LncRNAs Reveal Immune Characteristics, Predict Prognosis and Oncology Treatment Outcome in Lower-Grade Gliomas

“…m5C methylation is regulated by “writer, reader, and eraser” regulators that affect tumor progression under abnormal conditions ( 51 , 52 ). A comprehensive analysis of m5C regulators and their associated lncRNAs can help clarify the role of m5C modification patterns on LGG tumor cells and guide more effective individualized therapeutic strategies.…”

ALYREF associated with immune infiltration is a prognostic biomarker in hepatocellular carcinoma

“…According to the staining intensity, they were divided into three categories: 1 (mild), 2 (moderate), and 3 (severe), respectively. The two scores are multiplied to get the final score: low expression group [1] , [2] , [3] , [4] and high expression group [6] , [7] , [8] , [9] , [10] , [11] , [12] . The objects are classified by pathologists who had no access to clinical data.…”

“…ALYREF has been found to be upregulated in a number of malignancies and is connected with poor prognosis, including bladder cancer, glioblastoma, and head and neck squamous cell carcinoma. [8] , [9] , [10] , [11] , [12] . Xue et al [13] have pointed out that ALYREF might be a prognostic factor for HCC.…”