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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.. [scRNAseq]

ABSTRACT: SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.. [scRNAseq]

PROVIDER: PRJNA750394 | ENA |

REPOSITORIES: ENA

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.. [scRNAseq]

Project description:Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.

2023-03-06 | GSE181000 | GEO

SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. [RNAseq]

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. [ChIPseq and Cut&Tag]

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.

Project description:SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. [RNAseq]

Project description:SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. [RNAseq]

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. [ChIPseq and Cut&Tag]

Project description:SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance. [ChIPseq and Cut&Tag]

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.

| S-EPMC10220073 | biostudies-literature

TFCP2L1 promotes GPX4-mediated ferroptosis to inhibit breast cancer cell proliferation and metastasis via the PI3K/AKT signaling pathway

Project description:Breast cancer represents the most prevalent form of malignant tumors among women. Despite the existence of numerous therapeutic methods, a significant portion of patients face a poor prognosis, highlighting the urgency in identifying new remedial targets. Here, we for the first time demonstrated that the CP2 family member TFCP2L1, a classical marker of embryonic stem cell maintenance, as a tumor suppressor in breast cancer. Patients with breast cancer have poorer prognoses when TFCP2L1 is expressed highly. Consistently, the expression of TFCP2L1 is higher in normal breast cells than those in breast cancer cell lines. Gain- and loss-of-function and xenograft tumor assay showed that overexpression of TFCP2L1 significantly inhibited both the proliferation and migration of breast cancer cells in vivo and in vitro. Conversely, the knockdown of TFCP2L1 promoted the proliferation and migration of breast cancer cells. Mechanistically, we found that TFCP2L1 suppresses breast cancer progression by directly inhibiting the expression of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. Therefore, inhibition of GPX4 by RSL3, an inducer of ferroptosis was able to promote the function of TFCP2L1 in breast cancer cells. On the other hand, transcriptome high-throughput exhibited that TFCP2L1 negatively regulated the activity of PI3K/AKT signaling pathway. Administration of SC79, an AKT activator, was capable of partially restoring the negative effects of TFCP2L1 on GPX4 transcription. Together, TFCP2L1 functions by directly or indirectly regulating GPX4-mediated ferroptosis, and may serve as a novel biomarker and potential therapeutic target for breast cancer.

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress

SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.

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

2023-03-06 | GSE181001 | GEO