Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PHF5A coordinates p300 for epigenetic regulation of lipogenesis to promote hepatocellular carcinoma progression

ABSTRACT: PHD-finger protein 5A (PHF5A) is a component of U2snRNP, which plays a critical role in mRNA splicing for recognizing the branch site. However, whether it also plays other functions independent of RNA splicing remains elusive. Here, we find that expression levels of PHF5A are significantly upregulated in hepatocellular carcinoma (HCC). Down-regulation of PHF5A restrains liver cancer cell proliferation in vitro and in vivo. RNA-sequencing analysis reveals that fatty-acid biosynthetic enzymes are major downstream targets of PHF5A in HCC. Through metabolomics analysis, we find that inhibition of PHF5A reduces free fatty acid and phospholipid synthesis, further suppressing plasma membrane function. Mechanistically, PHF5A acts as a transcription co-factor of the p300 acetyltransferase for the H3K27 acetylation (Ac) and promotes H3K27Ac-dependent lipogenic genes expression. Our findings demonstrated a surprising splicing-independent role of PHF5A in transcriptional regulation of lipid metabolism for HCC progression and provided a new strategy for HCC therapy by blocking the interaction of PHF5A and p300.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167023 | GEO | 2021/10/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A

Project description:The process utilized by cancer cells for adapting to cellular stress is a key point for carcinogenesis. Alternative pre-mRNA splicing induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. However, the protein post-translational modification, especially protein acetylation on pre-mRNA splicing processes under stress is unknown. Here, we uncovered a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHD finger-like domain-containing protein 5A (PHF5A/SF3b14b), a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses. P300 and HDAC6 regulate PHF5A acetylation levels. PHF5A acetylation strengthens the interaction among U2 snRNPs, and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer patients. Our findings uncovered a novel mechanism of anti-stress pathway that acetylation on PHF5A promotes the cancer cells capacity for stress resistance and consequently contributes to colon carcinogenesis.

2018-11-22 | GSE122761 | GEO

Transcriptome-wide identification of transcripts regulated by PHF5A in colorectal cancer cells

Project description:Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here we demonstrated that PHF5A, a component of U2 snRNPs, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS, and established PHF5A as potential therapeutic target.

2021-07-16 | GSE180042 | GEO

Overlapping roles of spliceosomal components SF3B1 and PHF5A in rice splicing regulation

Project description:The SF3B complex, a multiprotein component of the U2 snRNP of the spliceosome, mediates branch point selection and facilitates spliceosome assembly and activation. Several splicing modulators bind the SF3B1 and PHF5A subunits of the SF3B complex and globally inhibit splicing. Engineered mutant variants of SF3B1 and PHF5A conferred tolerance to splicing inhibitors with only minor effects on gene expression and AS.

2021-04-11 | GSE153234 | GEO

Splicing Modulators Act at the Branch Point Adenosine Binding Pocket Defined by the PHF5A-SF3b Complex

Project description:Developing small-molecule splicing modulators represents a promising therapeutic approach for various diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that target SF3B1 in the SF3b subcomplex. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to these modulators, suggesting a common site of interaction. Whole-transcriptome RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but alters the action of splicing modulators from inducing intron-retention to exon-skipping. Relative intron strength to splicing inhibition correlates with the differential in GC content between adjacent introns and exons, leading to this differential global splicing pattern. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Structural analysis of the cryo-EM spliceosome Bact complex shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these splicing modulators, which interact with the aromatic side-chain of PHF5A-Y36. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these small-molecule splicing modulators, offering insights to modulate splicing.

2017-05-25 | GSE96917 | GEO

PHF5A coordinates p300 for epigenetic regulation of lipogenesis to promote hepatocellular carcinoma progression

Project description:PHF5A coordinates p300 for epigenetic regulation of lipogenesis to promote hepatocellular carcinoma progression

| PRJNA702753 | ENA

SIRT7-induced PHF5A de-crotonylation regulates ageing progress through alternative splicing-mediated downregulation of CDK2

Project description:Dysregulation of protein post-translational modification (PTM) can lead to a variety of pathological process, such as abnormal sperm development, malignant tumorigenesis, depression, and ageing process. SIRT7 is a NAD + dependent protein deacetylase. Besides known deacetylation, SIRT7 may also have the capacity to remove other acylation. However, the roles of SIRT7-induced other de-acylation in ageing is still largely unknown. Here, we found that the expression of SIRT7 was significantly increased in senescent fibroblasts and aged tissues. Knockdown or overexpression of SIRT7 can inhibit or promote fibroblast senescence. Knockdown of SIRT7 led to increased pan- lysine crotonylation (Kcr) levels in senescent fibroblasts. Using modern mass spectrometry (MS) technology, we identified 5149 Kcr sites across 1541 protein in senescent fibroblasts, providing the largest crotonylome dataset to date in senescent cells. Specifically, among the identified protein, we found SIRT7 de-crotonylated PHF5A, an alternative splicing factor, at K25. De-crotonylation of PHF5A K25 contributed to decreased CDK2 expression by Retained Intron (RI) induced abnormal alternative splicing, thereby accelerating fibroblasts senescence, supporting a key role of PHF5A K25 de-crotonylation in ageing. Collectively, our data revealed the molecular mechanism of SIRT7-induced k25 decrotonylation of PHF5A regulating aging, and provide new ideas and molecular targets for drug intervention in cellular ageing and the treatment of aging-related diseases, indicating that protein crotonylation has important implication in the regulation of ageing progress.

2022-02-17 | PXD027232 | Pride

Nascent transript profiling upon in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed nascent RNA profiling using global run-on sequncing in mouse ESCs under conditions of self-renewal, differentiation and Phf5a knockdown. These results revealed that genes positively regulated by Paf1 in ESCs exibit RNA elongation pausing on their promoters. We used conditions of self-renewal, differentiation, Phf5a knockdown and Paf1 knockdown to monitor nascent transcript expression changes during Phf5a depletion using global run-on RNA sequencing (GRO-seq). These results revealed that Phf5a through the control of Paf1 complex regulates pause release and elongation of pluripoency-associated genes in embryonic stem cells.

2016-08-31 | GSE73441 | GEO

Gene expression profiling using RNA-sequencing in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed gene expression profiling using RNA-sequncing in mouse ESCs under conditions of self-renewal, Phf5a knockdown and Paf1 knockdown. These results revealed that Phf5a and Paf1 regulate similar gene expression signatures in mouse ESCs.

2016-08-31 | GSE86248 | GEO

Characterization of Paf1 complex occupancy in mouse myoblasts and myotubes under control conditions or Phf5a knockdown

Project description:Phf5a regulates occupancy of Paf1 complex in mouse myotubes. In this study we assayed for genome-wide localization of Leo1 subunit of the Paf1 complex in mouse myoblasts or myotubes under conditions of shControl or shPhf5a knockdown. These results revealed that downregualtion of Phf5a results in significant decrease of Leo1 binding to its targets in myotubes.

2016-08-31 | GSE86249 | GEO

Characterization of Paf1 complex occupancy in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed for genome-wide localization of Paf1, Leo1 and Cdc73 subunits of the Paf1 complex in mouse ESCs under conditions of shControl and shPhf5a knockdown. These results revealed that downregualtion of Phf5a results in the significant decrease of Paf1 complex binding to its targets in ESCs.

2016-08-31 | GSE73445 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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