Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MTR4 drives tumorigenesis of hepatocellular carcinoma by controlling alternative splicing of metabolic genes through PTBP1 recruitment

ABSTRACT: Aberrant alternative splicing (AS) is implicated in cancer metabolic reprogramming that supplies cancer cells with energy and substrates for biosynthesis. Therefore, the elucidation of the mechanism underlying aberrant AS in cancer cells is important for developing specific and effective therapy. We demonstrated that MTR4, a RNA helicase important for RNA quality surveillance, is frequently overexpressed in hepatocellular carcinoma (HCC) and is correlated with increased glycolysis and poor prognosis of HCC patients. MTR4 is required for tumorigenesis of HCC cells by promoting glycolysis and expression of glycolytic genes. MTR4 binds to specific motifs of pre-mRNAs, including those of the key glycolytic genes, and regulates their AS by recruiting PTBP1. We discovered that MTR4 is a direct transcriptional target of c-Myc, suggesting that MTR4 mediates the metabolic function of c-Myc in HCC. These findings reveal mechanisms driving cancer-specific AS profile and present MTR4 as a specific therapeutic target for treating HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129263 | GEO | 2019/12/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Rip-seq of MTR4 in PLC/PRF5

Project description:Metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis by providing cancer cells with energy and substrates of biosynthesis, and also plays a key role in inducing immune suppressive tumor microenvironment that inhibits tumor immunotherapy. Therefore, to develop more effective cancer therapy, it is important to elucidate mechanisms that control cancer metabolic switch. MTR4 is a RNA helicase associated with nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrated that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and this predicts poor prognosis of HCC patients. MTR4 is required for HCC tumorigenesis by maintaining cancer metabolic switch. Mechanistically, MTR4 is required for the expression of critical glycolytic proteins such as GLUT1 and PKM2 by binding to their pre-mRNA and ensuring correct alternative splicing. c-Myc binds to the promoter of MTR4 gene and is required for MTR4 expression, indicating that MTR4 is a key mediator of c-Myc function in promoting cancer metabolism. These findings reveal an important pathway to drive cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.

2019-12-19 | GSE129261 | GEO

tiling hen2 and mtr4-HEN2 is a cofactor of the nuclear exosome in Arabidopsis

Project description:til-ath-2011_3 - tiling hen2 and mtr4 - Identification and comparison of the RNA substrates that accumulate in hen2 and mtr4 mutants. Total RNA extracted from WT, hen2 and mtr4 mutants was used for oligo-dT primed cDNA preparation. Samples were hybridised to NimbleGen whole genome tiling arrays. 8 dye-swapped samples. Gene knockout, genotype comparison, normal vs. transgenic comparison.

2013-06-30 | E-GEOD-48178 | biostudies-arrayexpress

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

Project description:Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. However, the precise mechanisms are not completely understood. Here we dissect how MNX1-AS1 reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the nucleus. We found that MNX1-AS1 expression was frequently overexpressed in hepatocellular carcinoma (HCC). In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. Upon EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, Glut1 and PDK1) are upregulated. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in vivo, indicative of the significant contribution of MNX1-AS1 to tumorigenesis. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

2022-11-23 | GSE213064 | GEO

USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

2021-07-27 | GSE158458 | GEO

Xrn1-sensitive lncRNAs accumulate upon inactivation of Dbp2 and Mtr4

Project description:To investigate the role of the helicases Dbp2 and Mtr4 in the decay of Xrn1-sensitive lncRNAs, we performed RNA-Seq in yeast cells lacking Dbp2 or depleted for Mtr4.

2023-07-27 | GSE235552 | GEO

Hydrogen-deuterium exchange mass spectrometry of wt Mtr4 with various RNA substrates

Project description:Mtr4 is a eukaryotic RNA helicase required for RNA decay by the nuclear exosome. Previous studies have shown how RNA enroute to the exosome threads through the highly conserved helicase core of Mtr4. Mtr4 also contains an arch domain, although details of potential interactions between the arch and RNA have been elusive. To understand the interaction of Saccharomyces cerevisiae Mtr4 with various RNAs, we have characterized RNA binding in solution using hydrogen-deuterium exchange mass spectrometry, and affinity and unwinding assays. We have identified RNA interactions within the helicase core that are consistent with existing structures and do not vary between tRNA, single-stranded RNA, and double-stranded RNA constructs. We have also identified novel RNA interactions with a region of the arch known as the fist or KOW. These interactions are important for RNA unwinding and vary in strength depending on RNA structure and length. They account for Mtr4 discrimination between different RNAs. These interactions further drive Mtr4 to adopt a closed conformation characterized by reduced dynamics of the arch arm and intra-domain contacts between the fist and helicase core.

2022-03-07 | PXD031962 | Pride

PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis

Project description:Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.

2024-11-05 | GSE262995 | GEO

tiling hen2 and mtr4-HEN2 is a cofactor of the nuclear exosome in Arabidopsis

2013-06-30 | GSE48178 | GEO

MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus

Project description:Recent in vitro reconstitution analyses have proven that the physical interaction between the exosome core and MTR4 helicase, which promotes the exosome activity, is maintained by either MPP6 or RRP6. However, knowledge regarding the function of MPP6 with respect to in vivo exosome activity remains scarce. Here we demonstrate a facilitative function of MPP6 that composes a specific part of MTR4-dependent substrate decay by the human exosome. Using RNA polymerase II-transcribed poly(A)+ substrate accumulation as an indicator of a perturbed exosome, we found functional redundancy between RRP6 and MPP6 in the decay of these poly(A)+ transcripts. MTR4 binding to the exosome core via MPP6 was essential for MPP6 to exert its redundancy with RRP6. However, at least for the decay of our identified exosome substrates, MTR4 recruitment by MPP6 was not functionally equivalent to recruitment by RRP6. Genome-wide classification of substrates based on their sensitivity to each exosome component revealed that MPP6 deals with a specific range of substrates, and highlights the importance of MTR4 for their decay. Considering recent findings of competitive binding to the exosome between auxiliary complexes, our results suggest that the MPP6-incorporated MTR4-exosome complex is one of multiple alternative complexes rather than the prevailing one.

2022-06-19 | GSE184274 | GEO

RNA Surveillance by the RNA Helicase MTR4 Determines Volume of Mouse Oocytes [polyA_RNA-seq]

Project description:Exosome is the main RNA surveillance and degradation pathway during oocyte growth. To figure out specific roles of RNA surveillance in oocyte growth, the pathway was destroied by deleting MTR4, the only known RNA helicase in exosome pathway. Poly(A) RNA-seq was performed to examine the global transcriptional changes.

2024-09-09 | GSE247848 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data