FUS and METTL3 collaborate to regulate RNA maturation, preventing unfolded protein response and promoting gastric cancer progression.

Liu, D; Ding, B; Liu, G; Yang, Z

FUS and METTL3 collaborate to regulate RNA maturation, preventing unfolded protein response and promoting gastric cancer progression.

Liu, D Ding, B Liu, G

Yang, Z

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Publisher:: SPRINGER-VERLAG ITALIA SRL
Publication Type:: Journal Article
Citation:: Clin Exp Med, 2024, 25, (1), pp. 15
Issue Date:: 2024-12-21

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Field	Value	Language
dc.contributor.author	Liu, D
dc.contributor.author	Ding, B
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.contributor.author	Yang, Z
dc.date.accessioned	2025-04-23T03:12:03Z
dc.date.available	2024-11-19
dc.date.available	2025-04-23T03:12:03Z
dc.date.issued	2024-12-21
dc.identifier.citation	Clin Exp Med, 2024, 25, (1), pp. 15
dc.identifier.issn	1591-8890
dc.identifier.issn	1591-9528
dc.identifier.uri	http://hdl.handle.net/10453/186967
dc.description.abstract	FUS-mediated alternative splicing and METTL3-regulated RNA methylation play crucial roles in RNA processing. The purpose of this study was to investigate the interactive roles of FUS and METTL3 in gastric cancer (GC) progression. RNA sequencing data were obtained from the TCGA-STAD dataset. Differentially expressed genes (DEGs) were analyzed across groups stratified by the medians of FUS, METTL3, and NEAT1, respectively. Endoplasmic reticulum (ER) stress markers PERK, IRE1, pIRE1, Bip, and CHOP, as well as related apoptosis stress markers PARP, cleaved-PARP, (Cleaved) Caspase 7, and (Cleaved) Caspase 3, were assessed through western blotting. Alternative splicing and N6-methyladenosine (m(6)A) methylation of specific genes were detected with MeRIP-PCR. Finally, in vivo experiments were conducted using nude mice bearing sh-FUS-transfected HGC27 xenograft tumors. FUS and METTL3 expression levels were elevated in GC tissues. A significant overlap of DEGs was observed between the FUS- and METTL3-stratified groups. These overlapping DEGs were predominantly enriched in mRNA processing and protein processing in the ER. ER stress and apoptosis were induced by sh-FUS or sh-METTL3, which was further enhanced by ER stress inducer tunicamycin in both MKN45 and HGC27 cells. Similarly, DEGs for NEAT1 high- and low-expressed groups were enriched in protein processing in the ER and spliceosome. To a lesser extent, ER stress was also induced by sh-NEAT1 and enhanced by tunicamycin in HGC27 cells. Furthermore, sh-FUS or sh-METTL3 influenced alternative splicing and methylation of specific mRNAs, including FUS, NEAT1, PCNA, MCM2, and BIRC5. Tumor progression was inhibited by sh-FUS in mice, and ER stress and apoptosis were induced, which were further enhanced by tunicamycin. FUS and METTL3 collaborate to facilitate RNA maturation. Inhibiting FUS or METTL3 promoted ER stress and apoptosis and inhibited progression in GC.
dc.format	Electronic
dc.language	eng
dc.publisher	SPRINGER-VERLAG ITALIA SRL
dc.relation.ispartof	Clin Exp Med
dc.relation.isbasedon	10.1007/s10238-024-01525-7
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences
dc.subject.classification	General Clinical Medicine
dc.subject.classification	3202 Clinical sciences
dc.subject.mesh	Stomach Neoplasms
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	RNA-Binding Protein FUS
dc.subject.mesh	Methyltransferases
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Mice
dc.subject.mesh	Unfolded Protein Response
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Disease Progression
dc.subject.mesh	Alternative Splicing
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Stomach Neoplasms
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Disease Progression
dc.subject.mesh	Methyltransferases
dc.subject.mesh	RNA-Binding Protein FUS
dc.subject.mesh	Apoptosis
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Alternative Splicing
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Unfolded Protein Response
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Stomach Neoplasms
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	RNA-Binding Protein FUS
dc.subject.mesh	Methyltransferases
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Mice
dc.subject.mesh	Unfolded Protein Response
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Disease Progression
dc.subject.mesh	Alternative Splicing
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.title	FUS and METTL3 collaborate to regulate RNA maturation, preventing unfolded protein response and promoting gastric cancer progression.
dc.type	Journal Article
utslib.citation.volume	25
utslib.location.activity	Italy
utslib.for	1103 Clinical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2025-04-23T03:12:00Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	25
utslib.citation.issue	1

Abstract:

FUS-mediated alternative splicing and METTL3-regulated RNA methylation play crucial roles in RNA processing. The purpose of this study was to investigate the interactive roles of FUS and METTL3 in gastric cancer (GC) progression. RNA sequencing data were obtained from the TCGA-STAD dataset. Differentially expressed genes (DEGs) were analyzed across groups stratified by the medians of FUS, METTL3, and NEAT1, respectively. Endoplasmic reticulum (ER) stress markers PERK, IRE1, pIRE1, Bip, and CHOP, as well as related apoptosis stress markers PARP, cleaved-PARP, (Cleaved) Caspase 7, and (Cleaved) Caspase 3, were assessed through western blotting. Alternative splicing and N6-methyladenosine (m(6)A) methylation of specific genes were detected with MeRIP-PCR. Finally, in vivo experiments were conducted using nude mice bearing sh-FUS-transfected HGC27 xenograft tumors. FUS and METTL3 expression levels were elevated in GC tissues. A significant overlap of DEGs was observed between the FUS- and METTL3-stratified groups. These overlapping DEGs were predominantly enriched in mRNA processing and protein processing in the ER. ER stress and apoptosis were induced by sh-FUS or sh-METTL3, which was further enhanced by ER stress inducer tunicamycin in both MKN45 and HGC27 cells. Similarly, DEGs for NEAT1 high- and low-expressed groups were enriched in protein processing in the ER and spliceosome. To a lesser extent, ER stress was also induced by sh-NEAT1 and enhanced by tunicamycin in HGC27 cells. Furthermore, sh-FUS or sh-METTL3 influenced alternative splicing and methylation of specific mRNAs, including FUS, NEAT1, PCNA, MCM2, and BIRC5. Tumor progression was inhibited by sh-FUS in mice, and ER stress and apoptosis were induced, which were further enhanced by tunicamycin. FUS and METTL3 collaborate to facilitate RNA maturation. Inhibiting FUS or METTL3 promoted ER stress and apoptosis and inhibited progression in GC.

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http://hdl.handle.net/10453/186967