G protein‐coupled oestrogen receptor promotes cell growth of non‐small cell lung cancer cells <i>via</i> YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 signalling

Shen, Yi; Li, Chong; Zhou, Lin; Huang, Jianan

doi:10.1111/jcmm.15997

Cited by 53 publications

(53 citation statements)

References 56 publications

(103 reference statements)

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“…Previous studies have linked m 6 A modifications to the development of lung cancer [ 41 ]. Several reports showed that m 6 A writers act as oncogenic-proteins to elevate global m 6 A levels [ 42 , 43 ], while m 6 A erasers decrease global m 6 A levels and act as tumor suppressors [ 44 ]. Compared to the writers and erasers, m 6 A readers are terminal effectors of the m 6 A modifications.…”

Section: Discussionmentioning

confidence: 99%

The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma

Xue

Zhang

et al. 2022

J Exp Clin Cancer Res

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Background Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Patient prognosis is poor, and the existing therapeutic strategies for LUAD are far from satisfactory. Recently, targeting N6-methyladenosine (m6A) modification of RNA has been suggested as a potential strategy to impede tumor progression. However, the roles of m6A modification in LUAD tumorigenesis is unknown. Methods Global m6A levels and expressions of m6A writers, erasers and readers were evaluated by RNA methylation assay, dot blot, immunoblotting, immunohistochemistry and ELISA in human LUAD, mouse models and cell lines. Cell viability, 3D-spheroid generation, in vivo LUAD formation, experiments in cell- and patient-derived xenograft mice and survival analysis were conducted to explore the impact of m6A on LUAD. The RNA-protein interactions, translation, putative m6A sites and glycolysis were explored in the investigation of the mechanism underlying how m6A stimulates tumorigenesis. Results The elevation of global m6A level in most human LUAD specimens resulted from the combined upregulation of m6A writer methyltransferase 3 (METTL3) and downregulation of eraser alkB homolog 5 (ALKBH5). Elevated global m6A level was associated with a poor overall survival in LUAD patients. Reducing m6A levels by knocking out METTL3 and overexpressing ALKBH5 suppressed 3D-spheroid generation in LUAD cells and intra-pulmonary tumor formation in mice. Mechanistically, m6A-dependent stimulation of glycolysis and tumorigenesis occurred via enolase 1 (ENO1). ENO1 mRNA was m6A methylated at 359 A, which facilitated it’s binding with the m6A reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and resulted in enhanced translation of ENO1. ENO1 positively correlated with METTL3 and global m6A levels, and negatively correlated with ALKBH5 in human LUAD. In addition, m6A-dependent elevation of ENO1 was associated with LUAD progression. In preclinical models, tumors with a higher global m6A level showed a more sensitive response to the inhibition of pan-methylation, glycolysis and ENO activity in LUAD. Conclusions The m6A-dependent stimulation of glycolysis and tumorigenesis in LUAD is at least partially orchestrated by the upregulation of METTL3, downregulation of ALKBH5, and stimulation of YTHDF1-mediated ENO1 translation. Blocking this mechanism may represent a potential treatment strategy for m6A-dependent LUAD.

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Section: Discussionmentioning

confidence: 99%

The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma

Xue

Zhang

et al. 2022

J Exp Clin Cancer Res

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“…Besides, circNOTCH1 served as endogenous competitive circRNA to compete for METTL14 binding. Due to the lack of METTL14, NOTCH1 mRNA appeared to be more stable and tended to be transcribed to high expression of NOTCH1, ultimately leading to initiate NOTCH1-mediated signal pathway 84 .…”

Section: Circrnas-rbps Interaction and Cancersmentioning

confidence: 99%

The Emerging Role of the Interactions between Circular RNAs and RNA-binding Proteins in Common Human Cancers

Jiang¹,

Xu²,

Hou³

et al. 2021

J. Cancer

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Circular RNAs (circRNAs) are a unique family of noncoding RNAs that could regulate multiple biological processes, which play a crucial role in carcinogenesis, progression and chemotherapy resistance of cancers. Growing studies have demonstrated that circRNAs act as novel biomarkers and therapeutic targets for cancers by sponging microRNAs (miRNAs). Up to date, another function of circRNAs, combining with RNA-binding proteins (RBPs), was uncovered. However, there is limit studies illustrating the underlying mechanism of circRNAs-RBPs interactions, as well as showing its roles in diverse types of cancers. In this review, we collected the biogenesis, properties of circRNAs, and then synthesize the connection between circRNAs and RBPs, and try to clarify its molecular mechanisms involving in the pathogenesis and progression of several common cancers, aiming to provide a brand-new insight to the prognosis and treatment strategy for cancers.

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“…Some of the molecules and cell signaling pathways activated by GPER are adenylyl cyclase, cAMP, calcium mobilization and MAPK. Other cell signaling pathways activated by GPER include EGFR/MARL transactivation, the Hippo/yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding domain (TAZ) pathway and phosphoinositide 3-kinase (PI3K)/Akt pathway ( Figure 3 ) [ 58 , 70 ]. A comprehensive discussion based on the studies conducted on GPER knockout mice confirmed the perception that GPER is in fact an ER with specific physiological functions mediated through nongenomic actions [ 70 ].…”

Section: G-protein-coupled Estrogen Receptors and Non-small Cell Lung Cancersmentioning

confidence: 99%

“…Studies by Avino and associates claimed that GPER-driven activation of insulin-like growth factor-I (IGF-I)/IGF-IR via ERK, p38 and Akt stimulation leads to migration of cancer cells [ 162 ]. A recent investigation by Shen and colleagues revealed an oncogenic activity of GPER on NSCLC cells via regulation of YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 mRNA signaling [ 58 ]. In contrast to these studies, some other investigations claimed that GPER activation inhibited migration of human NSCLC cells via suppressed IKK-β/NF-κB signaling pathways [ 57 ].…”

Section: G-protein-coupled Estrogen Receptors and Non-small Cell Lung Cancersmentioning

confidence: 99%

“…In addition, under NSCLC aggravated state, cytoplasmic GPER expression was found as being correlated with more advanced cancer stages (IIIA-IV), lymph node metastasis and poor differentiation [ 53 ]. A number of progrowth and pro-proliferative pathways are activated by the ligand-bound GPER and thereby activate tumor/cancer progression [ 55 , 56 , 57 , 58 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Estrogens and Various Estrogen-Related Receptors against Non-Small Cell Lung Cancers: A Perspective

Maitra

Malik

Mukherjee

2021

Cancers

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Non-small cell lung cancers (NSCLCs) account for ~85% of lung cancer cases worldwide. Mammalian lungs are exposed to both endogenous and exogenous estrogens. The expression of estrogen receptors (ERs) in lung cancer cells has evoked the necessity to evaluate the role of estrogens in the disease progression. Estrogens, specifically 17β-estradiol, promote maturation of several tissue types including lungs. Recent epidemiologic data indicate that women have a higher risk of lung adenocarcinoma, a type of NSCLC, when compared to men, independent of smoking status. Besides ERs, pulmonary tissues both in healthy physiology and in NSCLCs also express G-protein-coupled ERs (GPERs), epidermal growth factor receptor (EGFRs), estrogen-related receptors (ERRs) and orphan nuclear receptors. Premenopausal females between the ages of 15 and 50 years synthesize a large contingent of estrogens and are at a greater risk of developing NSCLCs. Estrogen—ER/GPER/EGFR/ERR—mediated activation of various cell signaling molecules regulates NSCLC cell proliferation, survival and apoptosis. This article sheds light on the most recent achievements in the elucidation of sequential biochemical events in estrogen-activated cell signaling pathways involved in NSCLC severity with insight into the mechanism of regulation by ERs/GPERs/EGFRs/ERRs. It further discusses the success of anti-estrogen therapies against NSCLCs.

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G protein‐coupled oestrogen receptor promotes cell growth of non‐small cell lung cancer cells via YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 signalling

Cited by 53 publications

References 56 publications

The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma

The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma

The Emerging Role of the Interactions between Circular RNAs and RNA-binding Proteins in Common Human Cancers

Targeting Estrogens and Various Estrogen-Related Receptors against Non-Small Cell Lung Cancers: A Perspective

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