The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1

Han, Han; Nakaoka, Hiroki J.; Hofmann, Line; Zhou, Jeff Jiajing; Yu, Clinton; Zeng, Lisha; Nan, Junyu; Seo, Gayoung; Vargas, Rebecca; Yang, Bing; Qi, Ruxi; Bardwell, Lee; Fishman, Dmitry A.; Cho, Ken W. Y.; Huang, Lan; Luo, Ray; Warrior, Rahul; Wang, Wenqi

doi:10.1038/s41556-021-00813-8

Cited by 29 publications

(18 citation statements)

References 85 publications

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“…Building on this result, the present study aims to further identify copper death genes that play a key role in gastric cancer. [15]A relatively low mutation frequency but high frequency of copy number alterations was found in CRGs, consistent with the previous study [27],which implicated that CRGs might be a potential treatment targets and served as a prognosis factors in GC patients.…”

Section: Discussionsupporting

confidence: 90%

Multi-omics Analysis of the Prognostic and Biological role of Cuproptosis-Related Gene in Gastric Cancer

Zhang

Liu

et al. 2023

Preprint

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Background Gastric cancer (GC)remains the third leading cause of cancer-related death. Cuproptosis has a high correlation with cancer development and progression, while Cuproptosis-related genes (CRGs) are rarely reported in GC. The aim of this multi-omics study was to investigate the prognostic value and biological functions of CRGs in GC, which may help guide precision medicine-based decision-making in GC patients. Methods RNA sequencing (RNA-seq) data, Copy number variations (CNV) data, and Single nucleotide variant (SNV) data were obtained from The cancer genome atlas (TCGA) database. Chi-squared test was adopted to screen differentially expressed CRGs (DE-CRGs) between samples from 14 kinds of carcinoma and adjacent tissue samples. Then, gastric cancer (GC) samples were divided into high- and low-expressed groups based on DE-CRGs for further overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-special survival (DSS) analysis. After single-gene Receiver operating characteristic (ROC) analysis, biomarkers of GC was obtained eventually. Besides, methylation sites related with biomarkers were acquired and survival analysis was performed based on those sites. Next, the correlation between immune cells and biomarkers was verified. Finally, we established miRNA-mRNA, TFs-mRNA, and co-expression networks to detect factors that have a regulating effect on biomarkers. Results Four DE-CRGs including CDKN2A, DLD, GLS, LIAS, and PDHB in most of the 14 cancers were screened out. Seven CRGs including GLS, LIAS, CDKN2A, DLD, LDAT, MTF1 and PDHA1 have a significant difference in the survival of GC patients. Next, single-gene ROC proved that PDHB, CDKN2A, LIAS, and GLS significantly correlate with GC prognosis. Three CRGs including LIAS, GLS, and CDKN2A were remain as biomarkers based on the results we got previously, and were used to generate a nomogram. After, 3 methylation sites with a significant survival relationship which include cg13601799, 07562918, and 07253264 were found. Then, we found that B cells native is significantly correlated with CDKN2A, 4 immune cells such as T cells regulatory (Tregs) are significantly correlated with GLS, and 2 immune cells such as T cells CD4 memory activated are significantly correlated with LIAS. Moreover, we found 10 miRNA in the miRNA-mRNA network and 3 TFs in the TFs-mRNA network have a significant correlation with OS. Finally, 20 enrichment functions were obtained such as cardiac septum development, collagen fibril organization, and sensory organ morphogenesis on the basis of the co-expression network. Conclusions 3 biomarkers with a prognosis prediction value of GC were found, and multi-factor regulatory networks was constructed to screen out 13 factors with regulating influences of biomarkers.

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Section: Discussionsupporting

confidence: 90%

Multi-omics Analysis of the Prognostic and Biological role of Cuproptosis-Related Gene in Gastric Cancer

Zhang

Liu

et al. 2023

Preprint

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“…Extensive studies have demonstrated that the Hippo pathway responds to many upstream metabolic signals 58 . Notably, Han et al 59 reported that the Hippo pathway plays an important role in heavy metal homeostasis by phosphorylating MTF1. Herein, we favored one model in which irontriggered LncRIM wired up the Hippo pathway, which, at least in part, exerted an oncogenic effect via the regulation of cellular iron levels.…”

Section: Discussionmentioning

confidence: 99%

LncRNA modulates Hippo-YAP signaling to reprogram iron metabolism

Fan

et al. 2023

Nat Commun

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Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM-NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM-NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development.

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“…For example, MTF1 promotes ATP7B expression by binding to the MRE in the promoter region of ATP7B to promote Wilson’s disease caused by copper overload ( 80 ). Phosphorylation of the kinase LATS of the Hippo pathway and inhibition of MTF1 protects cells from heavy metal-induced cytotoxicity ( 81 ). Thus, MTF1 primarily responds to excess copper levels in RA, and the hypoxic environment affects multiple pathological aspects of RA.…”

Section: Relationship Between Cuproptosis and Ramentioning

confidence: 99%

Cuproptosis and cuproptosis–related genes in rheumatoid arthritis: Implication, prospects, and perspectives

et al. 2022

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Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients’ physical and mental health, leading to chronic synovitis and destruction of bone joints. Although various available clinical treatment options exist, patients respond with varying efficacies due to multiple factors, and there is an urgent need to discover new treatment options to improve clinical outcomes. Cuproptosis is a newly characterized form of cell death. Copper causes cuproptosis by binding to lipid-acylated components of the tricarboxylic acid cycle, leading to protein aggregation, loss of iron-sulfur cluster proteins, and eventually proteotoxic stress. Targeting copper cytotoxicity and cuproptosis are considered potential options for treating oncological diseases. The synovial hypoxic environment and the presence of excessive glycolysis in multiple cells appear to act as inhibitors of cuproptosis, which can lead to excessive survival and proliferation of multiple immune cells, such as fibroblast-like synoviocytes, effector T cells, and macrophages, further mediating inflammation and bone destruction in RA. Therefore, in this study, we attempted to elaborate and summarize the linkage of cuproptosis and key genes regulating cuproptosis to the pathological mechanisms of RA and their effects on a variety of immune cells. This study aimed to provide a theoretical basis and support for translating preclinical and experimental results of RA to clinical protocols.

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The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1

Cited by 29 publications

References 85 publications

Multi-omics Analysis of the Prognostic and Biological role of Cuproptosis-Related Gene in Gastric Cancer

Multi-omics Analysis of the Prognostic and Biological role of Cuproptosis-Related Gene in Gastric Cancer

LncRNA modulates Hippo-YAP signaling to reprogram iron metabolism

Cuproptosis and cuproptosis–related genes in rheumatoid arthritis: Implication, prospects, and perspectives

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