YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63–GPX2 Axis and ROS Accumulation

Huang, Hsin‐Yi; Zhang, Wenjing; Pan, Yafang; Gao, Yijun; Deng, Lei; Li, Fuming; Li, Fēi; Ma, Xueyan; Hou, Shenda; Xu, Jing; Li, Peixue; Li, Xiaoxun; Hu, Guohong; Cheng, Li; Chen, Haiquan; Zhang, Lei; Ji, Hongbin

doi:10.1158/0008-5472.can-17-0449

Cited by 72 publications

(74 citation statements)

References 50 publications

(59 reference statements)

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“…In that study, ΔNp63 and AKT inhibition were shown to modulate YAP1. Recent studies indicate that the function or stability of ΔNp63 and YAP1 can be disrupted by natural isothiocynates such as sulforaphane, and by digitoxin, indicating potential as targets for chemoprevention or therapy (Fisher et al, 2017; Huang et al, 2017). We discovered that predominant expression of ΔNp63 isoforms and embedded miR-944 by SCC is correlated with decreased methylation of CpGs at the alternative TSS compared to those of the TSS for the TAp63 isoforms.…”

Section: Discussionmentioning

confidence: 99%

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Campbell¹,

Yau²,

Bowlby³

et al. 2018

Cell Reports

258

299

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SUMMARY This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Campbell¹,

Yau²,

Bowlby³

et al. 2018

Cell Reports

258

299

View full text Add to dashboard Cite

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“…Knockdown of GPX2 contributes to increase reactive oxygen species-(ROS-) dependent caspase activation in LUAD cells [8]. Huang et al [9] also found YAP suppresses lung squamous cell carcinoma progression via downregulation of GPX2 and ROS accumulation. In our previous works, GPX2 was screened to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing (data not shown) [10], but its specific functions and potential mechanisms are not yet clear.…”

Section: Introductionmentioning

confidence: 99%

Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma

Jiao

et al. 2020

Oxidative Medicine and Cellular Longevity

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The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.

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“…Inactivation of this pathway is closely related to the occurrence and development of multiple tumors [7]. Most studies have found that YAP/TAZ are abnormally overexpressed in tumors and promote tumorigenesis, and considered as carcinogenic genes in many solid cancers [8–10], even though some evidences indicate that YAP/TAZ functions as tumor suppressors [11, 12]. Immunohistochemical staining revealed that the high expression of YAP/TAZ was mainly detected in the tumor cell nuclei [13–16].…”

Section: Introductionmentioning

confidence: 99%

The role of YAP/TAZ activity in cancer metabolic reprogramming

et al. 2018

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In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.

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YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63–GPX2 Axis and ROS Accumulation

Cited by 72 publications

References 50 publications

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma

The role of YAP/TAZ activity in cancer metabolic reprogramming

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