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The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer

ABSTRACT: The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer

PROVIDER: PRJNA998370 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25385113_1.fastq.gz	Fastqsanger.gz
	SRR25385113_2.fastq.gz	Fastqsanger.gz
	SRR25385114_1.fastq.gz	Fastqsanger.gz
	SRR25385114_2.fastq.gz	Fastqsanger.gz
	SRR25385115_1.fastq.gz	Fastqsanger.gz

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The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [RNA-Seq]

Project description:Prostate cancer (PC) is the most common tumour diagnosis and a serious threat to the lives of men worldwide. It is well recognized that androgens play a unique role in prostate cancer and thus endocrine therapy, represented by androgen deprivation therapy (ADT), is a cornerstone of prostate cancer treatment. However, after ADT treatment, it is inevitable that a number of changes will occur leading from hormone sensitive prostate cancer to castration-resistant prostate cancer (CRPC). RB1 deletion, which is only present in 21% of the population, is the only genomic factor associated with the prognosis of androgen receptor signaling inhibitor therapy. We previously reported that phosphorylated RB has the ability to inhibit p65 in prostate cancer, thereby promoting immune tumour escape and increasing sensitivity to radiotherapy. The N-terminal end of RB also enhances the sensitivity of CDK4/6 inhibitors by recognizing the FXXXV amino acid motif on HDAC5 to down-regulate cell cycle-related genes. Recently, it has been shown that TRIM28 binds to and mediates the ubiquitinated degradation of RB protein. However, the relationship between TRIM24 and RB remains a mystery. In this study, we found that the phosphorylated RB N-terminal can interact with TRIM24 to form a complex that enhances AR signaling. And RB/TRIM24 used DUSP2 as an intermediate bridge to activate the mTOR pathway and promote prostate cancer progression. Finally, we also designed RB-linker-protac, which can attenuate TRIM24 protein levels and inactivate the mTOR signaling pathway, thereby inhibiting prostate cancer. This provides new insights into the treatment of prostate cancer.

2024-05-21 | GSE237930 | GEO

The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [ChIP-Seq]

2024-05-22 | GSE238209 | GEO

The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [RNA-Seq]

Project description:The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [RNA-Seq]

| PRJNA997255 | ENA

The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [ChIP-Seq]

Project description:The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [ChIP-Seq]

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Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates c-Met and TRIM24 as therapeutic targets

Project description:Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature revealed strong correlation with human MpBC tumors and MpBC xenograft (PDX) models. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC PDX tumorspheres revealed the therapeutic potential of targeting TRIM24. Altogether, global expression, single-cell immunophenotyping and mechanistic studies of tumors and MpBC PDX nominated TRIM24-activated c-MET/PI3K/mTOR pathways and TRIM24, which were validated as potential MpBC therapeutic targets.

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The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-22 | GSE238211 | GEO

VL30 retro-transposons are TRIM24-repressed enhancers that generate non-coding RNA to regulate gene expression in mouse hepatocytes. [RNA-Seq]

Project description:TRIM24 and TRIM33 interact to form a corepressor complex that suppresses murine hepatocellular carcinoma (HCC). TRIM24 and TRIM33 cooperatively repress retinoic acid receptor dependent activity of VL30 retro-transposons in hepatocytes in vivo. In TRIM24 knockout hepatocytes, VL30 long terminal repeats (LTRs) generate enhancer (e)RNAs and act as surrogate promoter and enhancer elements deregulating expression of neighbouring genes. We show that a VL30 LTR-derived eRNA is essential to activate the lipocalin 13 gene in hepatocytes in vivo. A further consequence of VL30 de-repression is the accumulation of retro-transcribed VL30 DNA in the cytoplasm of TRIM24-mutant hepatocytes and activation of the viral defence/interferon response. VL30 activation therefore modulates gene expression via the enhancer activity of the LTRs and by activation of the interferon response. Both of these processes are genetically linked to HCC development suggesting that VL30 repression by TRIM24 plays an important role in tumour suppression. RNA profiles in liver of wild type (WT) and Trim24-/- mice by deep sequencing using Illumina GAIIx.

2013-01-01 | E-GEOD-39851 | biostudies-arrayexpress

VL30 retro-transposons are TRIM24-repressed enhancers that generate non-coding RNA to regulate gene expression in mouse hepatocytes. [ChIP-Seq]

Project description:TRIM24 and TRIM33 interact to form a corepressor complex that suppresses murine hepatocellular carcinoma (HCC). TRIM24 and TRIM33 cooperatively repress retinoic acid receptor dependent activity of VL30 retro-transposons in hepatocytes in vivo. In TRIM24 knockout hepatocytes, VL30 long terminal repeats (LTRs) generate enhancer (e)RNAs and act as surrogate promoter and enhancer elements deregulating expression of neighbouring genes. We show that a VL30 LTR-derived eRNA is essential to activate the lipocalin 13 gene in hepatocytes in vivo. A further consequence of VL30 de-repression is the accumulation of retro-transcribed VL30 DNA in the cytoplasm of TRIM24-mutant hepatocytes and activation of the viral defence/interferon response. VL30 activation therefore modulates gene expression via the enhancer activity of the LTRs and by activation of the interferon response. Both of these processes are genetically linked to HCC development suggesting that VL30 repression by TRIM24 plays an important role in tumour suppression. Examination of H3k4me3 and RNA pol II in liver by deep sequencing.

2013-01-01 | E-GEOD-39852 | biostudies-arrayexpress

Readout of histone methylation by Trim24 locally restricts chromatin opening by p53

Project description:The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually diverse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dependence for p53 regulation. Here, we show that the ability of p53 to open chromatin and activate its target genes is indeed locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated lysine 4 of histone H3, thereby preferentially locating to those p53 sites that reside in closed chromatin, while it is deterred from accessible chromatin by lysine 4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to impact gene expression as a function of the local chromatin state. These findings link histone methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors which locally modulate TF function.

2023-05-05 | PXD039553 | Pride

Chromatin opening by p53 is confined by Trim24 in a histone methylation-dependent manner [ATAC-seq]

Project description:Chromatin modifications are thought to provide additional context dependence for sequence-based gene activation. Binding sites of the transcription factor (TF) and important tumor suppressor p53 are unusually diverse with regards to their chromatin accessibility and histone modifications, suggesting different modes of binding. Here, we show that the ability of p53 to open chromatin and activate its target genes upon DNA damage is locally restricted by its cofactor Trim24. The histone-binding domains of Trim24 limit the role of p53 at closed chromatin but not at accessible chromatin where Trim24 is blocked by histone 3 methylation at lysine 4. In turn p53 regulates gene expression as a function of the naïve chromatin state prior to activation. These findings establish a set of p53 response genes in closed chromatin that are Trim24-regulated and illustrate how histone modification sensing cofactors bridge local chromatin state and TF potency.

2023-04-30 | GSE200582 | GEO

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