ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development

Lang, Liwei; Loveless, Reid; Dou, Jingtao; Lam, Tiffany; Chen, Alex; Wang, Fang; Sun, Li; Juarez, Jakeline; Qin, Zhaohui S.; Saba, Nabil F.; Shay, Chloe; Teng, Yong

doi:10.1186/s13046-022-02274-9

Cited by 18 publications

(27 citation statements)

References 61 publications

(90 reference statements)

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“…Enzymes are crucial to metabolism, allowing the fine regulation of metabolic pathways to maintain a constant set of conditions in response to changes in the cell’s environment. The glycolysis pathway and its enzyme genes are highly conserved, playing critical roles in physiological and pathological processes [ 11 , 21 ]. ENO2 is a cytoplasmic glycolytic enzyme that plays its own role in glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…All cell lines were maintained in culture no more than 10 passages according to the supplier’s instructions. Human telomerase-immortalized tonsillar keratinocytes hTERT HAK Clone 41 were a gift from Dr. A. Klingelhutz and Dr. J. Lee (University of Iowa, Iowa City, IA) and cultured in KSFM with 0.2 ng/ml EGF and 30 μg/ml bovine pituitary extract [ 21 ]. Human primary HNSCC specimens of paraffin-embedded tissue blocks were obtained from the University-Town Hospital of Chongqing Medical University, China.…”

Section: Methodsmentioning

confidence: 99%

“…IHC assays were performed as we previously described [ 11 , 21 ]. Briefly, slides were deparaffinized, rehydrated, incubated in 3% H 2 O 2 to block endogenous peroxidase activity.…”

Section: Methodsmentioning

confidence: 99%

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Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Gao

Yang

Tang

et al. 2023

J Exp Clin Cancer Res

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Background Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear. Methods Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor. Results ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model. Conclusion Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Gao

Yang

Tang

et al. 2023

J Exp Clin Cancer Res

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“…Cholesterol plays a key role in pathways governing carcinogenesis and malignant progression. High expression levels of cholesterogenic genes were associated with human HNSCC development and supported poor prognosis [ 44 – 47 ]. Emerging evidence supports these observations.…”

Section: Discussionmentioning

confidence: 99%

Prognosis-related molecular subtyping in head and neck squamous cell carcinoma patients based on glycolytic/cholesterogenic gene data

Zhou

Tang

et al. 2023

Cancer Cell Int

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Background Head and neck squamous cell carcinoma (HNSCC) remains an unmet medical challenge. Metabolic reprogramming is a hallmark of diverse cancers, including HNSCC. Methods We investigated the metabolic profile in HNSCC by using The Cancer Genome Atlas (TCGA) (n = 481) and Gene Expression Omnibus (GEO) (n = 97) databases. The metabolic stratification of HNSCC samples was identified by using unsupervised k-means clustering. We analyzed the correlations of the metabolic subtypes in HNSCC with featured genomic alterations and known HNSCC subtypes. We further validated the metabolism-related subtypes based on features of ENO1, PFKFB3, NSDHL and SQLE expression in HNSCC by Immunohistochemistry. In addition, genomic characteristics of tumor metabolism that varied among different cancer types were confirmed. Results Based on the median expression of coexpressed cholesterogenic and glycolytic genes, HNSCC subtypes were identified, including glycolytic, cholesterogenic, quiescent and mixed subtypes. The quiescent subtype was associated with the longest survival and was distributed in stage I and G1 HNSCC. Mutation analysis of HNSCC genes indicated that TP53 has the highest mutation frequency. The CDKN2A mutation frequency has the most significant differences amongst these four subtypes. There is good overlap between our metabolic subtypes and the HNSCC subtype. Conclusion The four metabolic subtypes were successfully determined in HNSCC. Compared to the quiescent subtype, glycolytic, cholesterogenic and mixed subtypes had significantly worse outcome, which might offer guidelines for developing a novel treatment strategy for HNSCC.

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“…ATAD3A also mediates the activation of RASindependent mitochondrial ERK1/2 signaling, which facilitates the development of head and neck cancer. ANXA1 acts as a damage-associated molecular pattern-linked molecule that promotes necroptosis (Lang et al, 2022). By binding to and stabilizing EphA2, ANXA1 induces the growth and metastasis of nasopharyngeal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Using Necroptosis-Associated Genes To Predict The Immune Microenvironment And Prognosis Of Bladder Urothelial Carcinoma

Liu

Yang

et al. 2022

Preprint

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PURPOSE Bladder urothelial carcinoma (BLCA), the most common urinary tract malignancy, has a high recurrence rate and poor survival at late stages. Necroptosis, a form of programmed cell death, is involved in cancer development and progression, but its function in BLCA prognosis remains unclear. This study sought to investigate the role of necroptosis in the development and prognosis of BLCA. METHODS Clinical information and RNA expression matrix data were obtained from the databases. Survival analysis was performed to obtain survival- and necroptosis-related genes and identify any that overlapped. Consensus clustering analysis was used to create different subgroups by combining the overlapping gene expression matrix and clinical information. The tumor immune microenvironment and immune status of the different subgroups were determined using ESTIMATE, MCPcounter, and ssGSEA analysis. We performed differential analysis on the gene expression matrix of molecular subpopulations to find and screen out differentially expressed genes (DEGs). GO, KEGG, GSVA, and GSEA analyses were used to elucidate the underlying mechanisms of the DEGs. Lasso Cox regression analysis was used to build a prognostic risk model and perform a pan-cancer analysis of the screened genes. The results were used to define potential roles for these genes in other cancers and assess the efficacy of the risk model. RESULTS Cluster analysis identified two subgroups, C1 and C2, with significantly different survival rates. ESTIMATE, MCPcounter, and ssGSEA analyses showed that high immune scores, tumor purity, and immune status were associated with poorer prognoses. GO and KEGG functional enrichment analyses indicated that DEGs were mainly focused on tumor proliferation, invasion, and immunity and GSEA analysis suggested that necroptosis may affect Toll-like receptor signaling pathways, MAPK cascade regulation of leukocyte trafficking, and cytokine-cytokine receptor interaction pathways. Lasso Cox regression analysis was used to model the prognostic risk while screening for representative necroptosis-associated genes, ANXA1, ATAD3A, and TRPC6, with high potential for survival prediction in BLCA patients. The pan-cancer analysis indicated that the three representative genes were also differentially expressed in other cancer types. CONCLUSION Expression of necroptosis-related genes such as ANXA1, ATAD3A, and TRPC6 correlate with the immune microenvironment of BLCA patients and have the potential for use in disease prognostics.

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ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development

Cited by 18 publications

References 61 publications

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Prognosis-related molecular subtyping in head and neck squamous cell carcinoma patients based on glycolytic/cholesterogenic gene data

Using Necroptosis-Associated Genes To Predict The Immune Microenvironment And Prognosis Of Bladder Urothelial Carcinoma

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