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A recurrently amplified long noncoding RNA in colorectal cancer regulates p53 protein stability through GRWD1/RPL11/MDM2 axis [RNA-seq]

ABSTRACT: By integrating genome-wide copy number alteration, RNA-seq and proteomics data from 589 colorectal cancer (CRC) patients, we revealed that chromosome 8q24.21 amplification is negatively correlated with p53 protein stability. Using siRNA and CRISPR activation screening, we pinpointed a novel long noncoding gene (PiHL, P53 inHibiting LncRNA) from 8q24.21 as a p53 negative regulator. PiHL is drastically upregulated in CRC and is an independent predictor of CRC poor prognosis. Further In vitro and In vivo models demonstrate that PiHL is crucial in maintaining cell proliferation and inhibiting cell apoptosis through a p53-depedent manner. Mechanistically, PiHL acts to promote p53 ubiquitination by sequestering RPL11 from MDM2, through enhancing GRWD1 and RPL11 complex formation. We further show that p53 can form a feedback loop with PiHL by directly binding to PiHL promoter and regulating its expression. Our study successfully illustrates how cancer cells hijack the PiHL-p53 axis to promote CRC progression and suggests PiHL as a potential therapeutic target in human CRCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124526 | GEO | 2019/12/31

REPOSITORIES: GEO

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A recurrently amplified long noncoding RNA in colorectal cancer regulates p53 protein stability through GRWD1/RPL11/MDM2 axis [RNA-seq]

Project description:A recurrently amplified long noncoding RNA in colorectal cancer regulates p53 protein stability through GRWD1/RPL11/MDM2 axis [RNA-seq]

| PRJNA512374 | ENA

Partial loss of Rpl11 in adult mice recapitulates Diamond-Blackfan anemia (DBA) and promotes lymphomagenesis

Project description:Diamond-Blackfan anemia (DBA) is characterized by anemia and cancer susceptibility, and is caused by mutations in ribosomal genes, including Rpl11. Here, we report that Rpl11-heterozygous embryos are not viable, and homozygous deletion of Rpl11 in adult mice results in death within a few weeks, accompanied by bone marrow aplasia and intestinal atrophy. Importantly, deletion of a single Rpl11 allele in adult mice results in anemia associated to decreased erythroid progenitors and defective erythroid maturation. These phenotypes are also present in mice transplanted with inducible heterozygous Rpl11 bone marrow, indicating a cell-autonomous role of RPL11 in erythropoiesis. Additionally, fibroblasts lacking one or both Rpl11 alleles show defective p53 activation upon ribosomal stress or DNA damage. Furthermore, fibroblasts and hematopoietic tissues from heterozygous Rpl11 mice present higher basal cMYC levels. Accordingly, heterozygous Rpl11 mice are highly susceptible to radiation-induced lymphomagenesis. We conclude that Rpl11-deficient mice recapitulate DBA disorder, including cancer predisposition. RNAseq profiles of bone marrow hematopoietic progenitors cells from WT (Rpl11+/+:: Tg.UbC-CreERT2) and LOX (Rpl11+/lox::Tb.Ub-CreERT2) mice, n=4 independent animals per genotype

2015-09-01 | E-GEOD-72537 | biostudies-arrayexpress

Partial loss of Rpl11 in adult mice recapitulates Diamond-Blackfan anemia (DBA) and promotes lymphomagenesis

2015-09-01 | GSE72537 | GEO

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

Project description:Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from patient samples that contain a wild-type p53 gene. We found that the MDM2 W329G mutant was resistant to the inhibitory effect of ribosomal protein L11 (RPL11) on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous mdm2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

2024-05-13 | GSE267150 | GEO

Genome-wide analysis of gene expression changes in mouse keratinocytes induced by treatment with DAPT

Project description:Analysis of gene expression changes that occur in keratinocytes during reprogramming when they are treated with DAPT, a small molecule gamma-secretase inhibitor. The hypothesis tested in the present study was that Notch inhibition by DAPT treatment would promote reprogramming by inhibiting p21 activity while leaving p53 expression intact. Results provide important information of the gene expression changes in response to DAPT treatment, such as changes in the expression of p21, p21-responsive genes, p53, p53-responsive genes involved in apoptosis, and Notch-responsive genes. Total RNA obtained from mouse keratinocytes transduced with reprogramming transcription factors and treated or not treated with DAPT for 4 days or 7 days.

2014-05-25 | E-GEOD-35090 | biostudies-arrayexpress

p53 C-terminal acetylation modulates apoptotic program

Project description:Advanced colorectal cancer (CRC) is an unresolved clinical problem. Epigenetic drugs belonging to the group of histone deacetylase inhibitors (HDACi) may combat CRC in rationally designed treatment schedules. Unfortunately, there is sparse evidence on molecular mechanisms and markers that determine cellular sensitivity to HDACi. Irinotecan is widely used to treat CRC and causes replication stress (RS) and DNA damage as topoisomerase-I inhibitor. We applied irinotecan and the class I HDACi entinostat (MS-275) to isogenic p53-positive and -negative CRC cells. Combinations of irinotecan and MS-275 evoke mitochondrial damage, caspase-mediated apoptosis, and RS-associated DNA damage synergistically and p53-dependently. Targeted mass spectrometry and immunoblot show that irinotecan induces phosphorylation, acetylation, and accumulation of p53 and its target genes. Addition of MS-275 augments the irinotecan-induced acetylation of C-terminal lysine residues of p53 but decreases its phosphorylation and p53 target gene induction. Furthermore, MS-275 increases the amount of acetylated p53 at mitochondria and dysregulates the expression of pro- and anti-apoptotic BCL2 proteins in irinotecan-treated cells. Regarding DNA repair, we see that MS-275 represses the homologous recombination (HR) filament protein RAD51, which limits DNA damage and pro-apoptotic effects of irinotecan. These data suggest that key class I HDAC-dependent functions of p53 in cells with RS are linked to mitochondrial damage and a breakdown of HR. Most importantly, combinations of irinotecan plus MS-275 also kill short-term primary CRC cell cultures and organoids from CRC patients but spare organoids of adjacent matched normal tissue. Thus, irinotecan/HDACi treatment is a promising new approach for the therapy of p53-proficient tumors with clinically tractable inhibitors.

2022-02-15 | PXD019999 | Pride

Next generation sequencing facilities quantitative analysis of SHARPIN knockout or non-target LoVo cells

Project description:Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer mortality worldwide. Further improvements are needed for the treatment of CRC. The E3 ubiquitin ligase is an enzyme that plays an important role in regulating protein expression levels via posttranslational ubiquitin-mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In this study, using comprehensive expression analysis involving spatial transcriptomic analysis with single-cell RNA sequencing in clinical CRC datasets, we identified the ubiquitin-associated protein Shank-associated RH domain interactor (SHARPIN) as a putative driver gene located on amplified chromosome 8q. SHARPIN was overexpressed in tumor cells, and high expression of SHARPIN in tumor tissues was positively correlated with lymphatic invasion and was independently predictive of a poor prognosis in CRC patients. In vitro and in vivo analyses using SHARPIN-overexpressing or -knockout CRC cells revealed that SHARPIN upregulated MDM2, resulting in subsequent downregulation of p53, which inhibits tumor cell apoptosis and promotes tumor growth in CRC. Furthermore, SHARPIN overexpression and significant effects on survival were observed in various cancers. In conclusion, SHARPIN is a novel driver gene that potentially promotes tumor growth following apoptosis inhibition in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.

2024-02-14 | GSE255286 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes in negative control and miR-1290 knockdown HCT116 cells

Project description:Colorectal cancer (CRC) ranks third in incidence and second in mortality among cancers worldwide. Emerging researches showed that microRNAs (miRNAs) play an important role in CRC progression. Here, we aimed to investigate the expression and regulatory mechanism of miR-1290 in CRC. miR-1290 is significantly overexpressed in CRC primary tissues and metastatic tissues compared to that in normal tissues, and up-regulated miR-1290 is correlated with poor overall survival (OS) of CRC patients. Functional experiments showed that miR-1290 can promote the proliferation, migration, invasion and inhibit apoptosis of CRC cells. Mechanistically, miR-1290 directly targets KLF9 and promotes the malignancy progression of CRC cells through regulating MMP9 and p53 expression, subsequently. In addition, high H3K4me3 levels in miR-1290 promoter region activate its transcription in CRC. In summary, our study demonstrated the expression and regulatory mechanism of miR-1290 in CRC which supports the notion that therapeutic targeting of miR-1290 may be a promising treatment approach for CRC patients.

2020-11-11 | GSE161186 | GEO

FIT Links c-Myc and P53 Acetylation by Recruiting RBBP7 During Carcinogenesis of Colorectal Cancer

Project description:Colorectal cancer (CRC) poses one of the most serious threat against human health worldwide, and abnormally expressed c-Myc and p53 are deemed the pivotal driving forces of CRC progression. Here we discovered a lncRNA FIT, which was down-regulated in CRC clinical samples, was transcriptionally suppressed by c-Myc and promoted CRC cells apoptosis by inducing FAS expression. FAS is a p53 target gene, and we found that FIT formed a trimer with RBBP7 and p53 which facilitated p53 acetylation and transcription. Moreover, FIT was capable of retarding CRC growth in mice xenograft model and positively relevant to FAS expression clinically. Thereby our study elucidated the role of lncRNA FIT in human colorectal cancer growth and provides a potential target for anti-CRC drugs.

2022-08-29 | GSE211804 | GEO

Genome-wide analysis of gene expression changes in mouse keratinocytes induced by treatment with DAPT

2014-05-25 | GSE35090 | GEO

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