Identification and Characterization of a Glucometabolic Prognostic Gene Signature in Neuroblastoma Based on N6-methyladenosine Eraser ALKBH5

Overview

Journal J Cancer

Specialty Oncology

Date 2022 May 6

PMID 35517412

Authors

Kezhe Tan

Wei Wu

Kai Zhu

Li Lu

Zhibao Lv

Affiliations

Soon will be listed here.

Abstract

Neuroblastoma (NB) is a pediatric cancer occurring in the peripheral nervous system. A demethylase, alkylation repair homolog protein 5 (ALKBH5), is one type of N6-methyladenosine (m6A) eraser that plays a tumor-suppressive role in a variety of cancers. The significance of carbohydrate metabolism in cancer has been intensively investigated over the years, but the correlation between ALKBH5 and glucose metabolism in NB remains to be elucidated. Based on the overlapped genes (DE-GRGs) of ALKBH5-related differentially expressed genes (ALKBH5-DEGs) in GSE62564 (n=498) and genes related to glucose metabolism (GRGs), a LASSO regression model was constructed. External validations with datasets (EGAS00001001308, n=139 & GSE16476, n=88) and the NB samples from Shanghai Children's Hospital (SCH) were performed. Meanwhile, biological and clinical utility, immune cell subtypes and drug sensitivity were assessed. ALKBH5 was significantly correlated with better overall survival (OS) in NB patients, and gene set enrichment analysis (GSEA) showed its enrichment in GO/ KEGG terms regarding glucose metabolism. 27 of the 31 DE-GRGs were included in the LASSO screen after the univariate analysis. A prognostic glucometabolic model including AHCY, NCAN, FBP2, GALNT3 and AKR1C2 was established with the internal and external validation with biological experiments: the high-risk subtype compared to the low-risk subtype showed oncogenic and MYCN-related malignancy, glucometabolic dysregulation, poor prognosis and immunosuppression. TGX-221 was predicted to be a potential therapeutic drug and validated to suppress NB oncogenes including MYCN, AHCY and NCAN and immunosuppressive DNMT1 in NB cells. ALKBH5 was closely related to glucometabolic processes, and our prognostic model had high application value in predicting & assessing the OS of NB patients, and even served potential drug targets.

Citing Articles

M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms.

Fang M, Ye L, Zhu Y, Huang L, Xu S Biomolecules. 2025; 15(2).

PMID: 40001461 PMC: 11853652. DOI: 10.3390/biom15020157.

Predictive role of SLC1A5 in neuroblastoma prognosis and immunotherapy.

Cheng J, Sun M, Dong X, Yang Y, Qin X, Zhou X BMC Cancer. 2025; 25(1):161.

PMID: 39875895 PMC: 11773968. DOI: 10.1186/s12885-025-13560-y.

Synergistic machine learning models utilizing ferroptosis-related genes for improved neuroblastoma outcome prediction.

Cheng J, Dong X, Yang Y, Qin X, Zhou X, Zhang D Transl Pediatr. 2025; 13(12):2164-2182.

PMID: 39822999 PMC: 11732634. DOI: 10.21037/tp-24-323.

Knowledge mapping and current trends of m6A methylation in the field of cancer.

Zhu C, Yang J, Zhang C, Wang Y, Wang J Heliyon. 2024; 10(4):e26262.

PMID: 38434062 PMC: 10906179. DOI: 10.1016/j.heliyon.2024.e26262.

CRISPR-Cas9 knockout screening identifies KIAA1429 as an essential gene in Ewing sarcoma.

Tan K, Lu W, Chen F, Shi H, Ma Y, Chen Z J Exp Clin Cancer Res. 2023; 42(1):250.

PMID: 37759224 PMC: 10537923. DOI: 10.1186/s13046-023-02828-5.

References

Liu J, Cheng J, Li L, Li Y, Zhou H, Zhang J . gene polymorphisms and neuroblastoma susceptibility in Chinese children: an eight-center case-control study. J Cancer. 2021; 12(8):2465-2471. PMC: 7974895. DOI: 10.7150/jca.54496. View

Wang L, Tan T, Durbin A, Zimmerman M, Abraham B, Tan S . ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry. Nat Commun. 2019; 10(1):5622. PMC: 6901540. DOI: 10.1038/s41467-019-13515-5. View

Li N, Gao W, Zhang Y, Ho M . Glypicans as Cancer Therapeutic Targets. Trends Cancer. 2018; 4(11):741-754. PMC: 6209326. DOI: 10.1016/j.trecan.2018.09.004. View

Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S . Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. Oncotarget. 2018; 8(63):106296-106310. PMC: 5739734. DOI: 10.18632/oncotarget.22435. View

Pinto N, Applebaum M, Volchenboum S, Matthay K, London W, Ambros P . Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol. 2015; 33(27):3008-17. PMC: 4567703. DOI: 10.1200/JCO.2014.59.4648. View

Chayka O, DAcunto C, Middleton O, Arab M, Sala A . Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells. J Biol Chem. 2014; 290(4):2198-212. PMC: 4303671. DOI: 10.1074/jbc.M114.624056. View

Valentijn L, Koster J, Zwijnenburg D, Hasselt N, van Sluis P, Volckmann R . TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet. 2015; 47(12):1411-4. DOI: 10.1038/ng.3438. View

Salem A, Alotaibi M, Mroueh R, Basheer H, Afarinkia K . CCR7 as a therapeutic target in Cancer. Biochim Biophys Acta Rev Cancer. 2021; 1875(1):188499. DOI: 10.1016/j.bbcan.2020.188499. View

Ding C, Yi X, Chen X, Wu Z, You H, Chen X . Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma. J Exp Clin Cancer Res. 2021; 40(1):164. PMC: 8111743. DOI: 10.1186/s13046-021-01942-6. View

10.

Matthay K, Maris J, Schleiermacher G, Nakagawara A, Mackall C, Diller L . Neuroblastoma. Nat Rev Dis Primers. 2016; 2:16078. DOI: 10.1038/nrdp.2016.78. View

11.

Ji Q, Chang L, Stanczyk F, Ookhtens M, Sherrod A, Stolz A . Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. Cancer Res. 2007; 67(3):1361-9. DOI: 10.1158/0008-5472.CAN-06-1593. View

12.

Ichikawa S, Imel E, Kreiter M, Yu X, Mackenzie D, Sorenson A . A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007; 117(9):2684-91. PMC: 1940239. DOI: 10.1172/JCI31330. View

13.

Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A . A mechanistic classification of clinical phenotypes in neuroblastoma. Science. 2018; 362(6419):1165-1170. PMC: 7875194. DOI: 10.1126/science.aat6768. View

14.

Yang W, Kim J, Jeong D, Hong Y, Park S, Yang Y . 3-Deazaadenosine, an S-adenosylhomocysteine hydrolase inhibitor, attenuates lipopolysaccharide-induced inflammatory responses via inhibition of AP-1 and NF-κB signaling. Biochem Pharmacol. 2020; 182:114264. DOI: 10.1016/j.bcp.2020.114264. View

15.

Sahasrabudhe N, Lenos K, van der Horst J, Rodriguez E, van Vliet S . Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3. Biol Chem. 2018; 399(7):649-659. DOI: 10.1515/hsz-2018-0120. View

16.

Tang J, Lu H, Yang Z, Li L, Li L, Zhang J . Associations between gene polymorphisms and neuroblastoma susceptibility in Chinese children. Transl Pediatr. 2021; 10(1):146-152. PMC: 7882302. DOI: 10.21037/tp-20-168. View

17.

Ji Q, Aoyama C, Nien Y, Liu P, Chen P, Chang L . Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling. Cancer Res. 2004; 64(20):7610-7. DOI: 10.1158/0008-5472.CAN-04-1608. View

18.

Yang Y, Hsu P, Chen Y, Yang Y . Dynamic transcriptomic mA decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018; 28(6):616-624. PMC: 5993786. DOI: 10.1038/s41422-018-0040-8. View

19.

Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z . The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021; 6(1):74. PMC: 7897327. DOI: 10.1038/s41392-020-00450-x. View

20.

Park M, Yang A, Lee J, Kim S, Roe J, Park M . GALNT3 suppresses lung cancer by inhibiting myeloid-derived suppressor cell infiltration and angiogenesis in a TNFR and c-MET pathway-dependent manner. Cancer Lett. 2021; 521:294-307. DOI: 10.1016/j.canlet.2021.08.015. View