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The SETD7-PDGFB-HRAS-ERK Axis Drives Ovarian Cancer Progression through Epigenetic Activation

ABSTRACT: The study aims to investigate the impact of SET domain-containing lysine methyltransferase 7 (SETD7) on the proliferation and migration of ovarian cancer cells, and to elucidate the molecular mechanism by which SETD7 promotes these malignant phenotypes through activation of the HRAS ERK signaling pathway. This research will provide novel theoretical foundations for the diagnosis and treatment of ovarian carcinoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342060 | GEO | 2026/09/20

REPOSITORIES: GEO

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The SETD7-PDGFB-HRAS-ERK Axis Drives Ovarian Cancer Progression through Epigenetic Activation

Project description:The SETD7-PDGFB-HRAS-ERK Axis Drives Ovarian Cancer Progression through Epigenetic Activation

| PRJNA1505514 | ENA

Combined inhibition of HRAS and MEK induces tumor regression and restores myogenic differentiation in HRAS-mutant rhabdomyosarcoma

Project description:Hyperactive RAS signaling drives tumorigenesis in PAX 3/7::FOXO1 fusion-negative rhabdomyosarcoma (FN-RMS). Despite the frequency of these mutations, indirect RAS pathway-directed therapies have been ineffective for RAS-driven RMS. Farnesyltransferase (FTase) inhibitors (FTIs), such as tipifarnib, inhibit HRAS membrane localization and blunt HRAS effector signaling, leading to an antitumor effect in HRAS-mutant FN-RMS preclinical models. Response to FTase inhibition is limited by adaptive feedback reactivation of ERK signaling and upregulation of wild-type (WT) RAS. We found that the combination of HRAS suppression with FTI and MEK inhibition (MEKi) impaired ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models. Co-targeting FTase and MEK restrained tumor progression and induced terminal myogenic differentiation. These findings highlight an effective combinatorial strategy and support its preclinical translation for patients with HRAS-mutant RMS.

2025-12-08 | GSE312030 | GEO

Kinome profiling of HRAS Q61K mutant SMS-CTR rhabdomyosarcoma cell line treated with tipifarnib

Project description:Hyperactive RAS signaling drives tumorigenesis in PAX 3/7::FOXO1 fusion-negative rhabdomyosarcoma (FN-RMS). Despite the frequency of these mutations, RAS pathway-directed therapies have been ineffective for RAS-driven RMS. Farnesyltransferase (FTase) inhibitors (FTIs), such as tipifarnib, inhibit HRAS membrane localization and blunt HRAS effector signaling, leading to an antitumor effect in HRAS-mutant FN-RMS preclinical models. Response to FTI is limited by adaptive feedback reactivation of ERK signaling and upregulation of wild-type (WT) RAS. We found that the combination of HRAS suppression with FTI and MEK inhibition (MEKi) impaired ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models. Co-targeting FTase and MEK restrained tumor progression and induced terminal myogenic differentiation. These findings highlight an effective combinatorial strategy and support its preclinical translation for patients with HRAS-mutant RMS. Here, kinome profiling was performed on the SMS-CTR(HRAS Q61K) RMS cell line after 24 or 48 hour exposure to 100 nM tipifarnib.

2026-02-12 | PXD062989 | Pride

Global analysis of methylation by SETD7 in the MM genome

Project description:We analyzed methylation by SETD7 in multiple myeloma using ChIP-seq.

2025-08-15 | GSE304199 | GEO

Essential Roles of SETD7 as Transcriptional Activator and Co-regulator of H3K36me in Cardiac Lineage Commitment

Project description:Coordinated epigenome alteration is fundamental for cardiac development. However, the precise mechanisms by which epigenetic modifying enzymes regulate cardiac development are still unclear. Here we identify SET domain containing protein 7 (SETD7) as a key regulator of cardiac differentiation. ChIP-seq reveals that SETD7 has distinct groups of target genes and regulates its stage-specific expression during cardiomyocyte differentiation, which is crucial for lineage commitment. We find SETD7 associates with stage-specific co-factors, such as SWI/SNF chromatin remodeling factors during mesodermal formation and transcription factor NKX2-5 in cardiac progenitor differentiation. Cross-analysis of epigenetic modifications shows that SETD7 recognizes and binds with active histone marker H3K36 methylation on gene-body region of its target genes. We further demonstrate SETD7 is required for functional properties of terminally differentiated cardiomyocytes. Together, our results suggest unidentified roles of SETD7 in cardiac lineage commitment and provide new insights into the crosstalk between epigenetic dynamics and epigenetic modifying enzymes.

2018-04-17 | GSE107785 | GEO

SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1 [ChIP-seq]

Project description:We recently reported that in prostate cancer LSD1 can demethylate the lysine 270 of FOXA1 to stabilize FOXA1 chromatin binding and thus can enhance the activities of AR and other transcription factors that require FOXA1 as a pioneer factor. However, the methyltransferase that can methylate FOXA1 and negatively regulate the LSD1-FOXA1 oncogenic axis remains unknown. SETD7 is initially identified as a transcriptional activator through methylating histone 3 lysine 4 but can also function as a methyltransferase on other non-histone substrates. However, its function in PCa remains poorly understood. In this study, we found that SETD7 confers tumor suppressor activity in PCa cells and that loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Mechanistically, we found that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as a methyltransferase of FOXA1-K270 to disrupt FOXA1-mediated transcription. Overall, our study provides novel mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.

2023-08-23 | GSE218092 | GEO

Normal mouse skin lacking Hras

Project description:Oncogenic activating mutations in Ras genes are among the most common drivers of human disease. Treating mouse skin with the chemical carcinogen DMBA induces a characteristic mutation in Hras at codon 61. To understand how skin responds to a constitutive lack of Hras, we generated a cohort of Hras knockout mice. A backcross was generated using male Mus spretus and female FVB/N Hras-/- mice; female F1 hybrids were mated with male FVB/N Hras -/- or Hras -/+ mice to generate a backcross population. This series contains mice that were Hras -/-. Mice were aged to 8 weeks and a tail skin sample was snap frozen.

2015-03-01 | E-GEOD-60769 | biostudies-arrayexpress

Normal mouse skin lacking Hras

2015-03-01 | GSE60769 | GEO

Transcription profiling of rat fibroblasts transformed with HRAS and treated with the demethylating agent 5-aza-2-deoxycytidine

Project description:Silencing of gene expression by methylation of CpG islands in regulatory elements is frequently observed in cancer. However, an influence of the most common oncogenic signalling pathways onto DNA methylation has not yet been investigated thoroughly. To address this issue, we identified genes suppressed in HRAS-transformed rat fibroblasts but up-regulated after treatment with the demethylating agent 5-Aza-CdR and with the MEK1,2 inhibitor U0126. Analysis of gene expression by microarray and Northern blot analysis revealed the MEK/ERK target genes clusterin, Mmp2, Ppicap, syndecan 4, Timp2, Thbs1 to be repressed in the HRAS-transformed FE-8 cells in a MEK/ERK- and in a methylation-dependent manner. Hypermethylation of putative regulatory elements in HRAS-transformed cells as compared to immortalized fibroblasts was detected within a CpG island 14.5 kb upstream of clusterin, within the clusterin promoter and within a CpG island of the Mmp2 promoter by bisulphite sequencing. Furthermore, hypermethylation of the clusterin promoter was observed ten days after induction of HRAS in immortalized rat fibroblasts and a clear correlation between reduced clusterin expression and hypermethlyation could also be observed in distinct rat tissues. These results suggest that silencing of individual genes by DNA methylation is controlled by oncogenic signalling pathways, yet the mechanisms responsible for initial target gene suppression are variable. Experiment Overall Design: Gene expression was analyzed in immortal (208F) and HRAS oncogene-transformed (FE8) rat fibroblasts after demethylation by 5-aza-2'-deoxycytidine. Genes potentially methylated in RAS-transformed cells were identified by bisulphite sequencing

2007-11-06 | E-GEOD-4427 | biostudies-arrayexpress

The SETD7–H3K4me1–APLNR Axis Couples Epigenetic Signaling to Orchestrate Endoderm Specification in Human Pluripotent Stem Cells

Project description:The differentiation of human pluripotent stem cells into definitive endoderm (DE), a pivotal event in embryonic development, remains incompletely elucidated with respect to its epigenetic control. Here, we identified SETD7, a histone H3K4 monomethyltransferase (H3K4me1), as dynamically upregulated during DE specification, with its expression correlating strongly with the key lineage marker SOX17. Genetic knockdown of SETD7 impaired DE formation, as evidenced by reduced expression of DE markers and disruption of APLNR-mediated PI3K/AKT/mTOR signaling—a phenotypic defect recapitulated by pharmacological inhibition of APLNR. Mechanistically, SETD7 facilitates H3K4me1 deposition at enhancer regions of APLNR, thereby promoting its transcriptional activation. Our findings unveil an epigenetic-regulatory axis wherein SETD7-mediated enhancer priming drives APLNR expression, ultimately activating the PI3K/AKT/mTOR cascade to promote endodermal commitment. Through an integrated approach incorporating doxycycline-inducible SETD7 knockdown in hESCs, pathway-specific pharmacology, ChIP-qPCR, and 3D organoid modeling, we decipher the spatiotemporal regulatory network governed by SETD7 during DE specification. This study highlights the critical crosstalk between histone modification landscapes and signal transduction during cell fate determination and establishes a novel strategy for manipulating differentiation trajectories.

2026-01-01 | GSE309012 | GEO

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