O-GlcNAcylation of RUNX1 promotes its stability and PDGF-BB-mediated resistance to CDK4/6 inhibitors in breast cancer
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture
SUBMITTER: 
YI ZHANG
LAB HEAD: Dr. Wenge
PROVIDER: PXD049409 | Pride | 2025-01-31
REPOSITORIES: pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| 1.raw | Raw | |||
| 1.xlsx | Xlsx | |||
| 2.raw | Raw | |||
| 2.xlsx | Xlsx | |||
| checksum.txt | Txt |
Items per page: 5 1 - 5 of 5 |
Similar Datasets
Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remain an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using Conditional medium co-culture, quantitative high-throughput combinational screen (qHTCS), and genomic sequencing, we report that the RUNX1-PDGFBB-AKt pathway was significantly elevated in palbociclib-resistance cells. Inhibition of this axis can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies RUNX1 with O-GlcNAcylation at Serine 252 (Ser252), thereby stabilizing RUNX1 protein expression, which is crucial in regulating PDGFBB expression. Significantly, clinical studies also confirm that RUNX1-PDGFBB-Akt pahtway was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which RUNX1-PDGFBB mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.
2025-01-30 | GSE264264 | GEO
Project description:CDK4/6 inhibition is the standard of care for estrogen receptor positive (ER+) breast cancer, although cytostasis is frequently observed, and new treatment strategies that enhance efficacy are required. We performed a genome-wide CRISPR screen to identify genetic determinants of CDK4/6 inhibitors sensitivity. Multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity. Depletion or inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and sensitised triple negative breast cancer models to palbociclib, with GPX4 null xenografts being highly sensitive to palbociclib. Palbociclib induced oxidative stress and disordered lipid metabolism with lipid peroxidation, leading to a ferroptosis-sensitive state. Lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 inhibition creates vulnerability to ferroptosis that could be exploited through combination with GPX4 inhibitors, enhancing sensitivity to CDK4/6 inhibition in breast cancer.
2023-06-20 | PXD043133 | Pride
Project description:RUNX1 gene chromosomal translocations and mutations are frequent in acute myeloid leukaemia, sometimes resulting in the aberrant expression of C-terminal-truncated RUNX1 proteins lacking the transactivation domain (TAD). Some AML patients anomalously over-express a RUNX1a splice variant with the same TAD deficit. We performed an in-depth in vitro study of the role of TAD-defective RUNX1 proteins in AML development in human hematopoietic/progenitor stem cells. Transformation ability, maturation phenotype and differentiation/proliferation effects were assessed. Short RUNX1 protein expression seemed to increase both proliferation and self-renewal capacity, disrupting the differentiation program and interfering with wild-type RUNX1b protein, in a dominant-negative, dose-dependent manner. Expression microarray analysis showed short RUNX1 and RUNX1/ETO models had similar aberrant expression patterns. Genes known to be broadly involved in self-renewal and leukemogenesis were found to be altered; specifically observed were overexpression of homeobox genes, downregulation of primitive erythroid genes and alterations in leukemogenic transcription factors. The Wnt/b-catenin and RhoA pathways were also observed to be altered, whereas short RUNX1 proteins appeared not to affect the Notch1 pathway, which is altered in the RUNX1/ETO model. Therefore, we propose that TAD-defective RUNX1 proteins may contribute to leukemogenesis and could form the basis of a new genetic category of AML. Comparative experiment: Human CD34+ hematopoietic cells gene expression was measured after TAD defective RUNX1 cDNA transfection vs empty vector transfection. Two independent experiments were performed for each protein model, using different cord blood donors for each experiment.
2014-01-01 | E-GEOD-48523 | biostudies-arrayexpress
Project description:Human histone deacetylase 3 (HDAC3) plays an important role in gene transcription in diseased human cells, such as leukemia. The t(8;21) chromosomal translocation is one of the most commonly observed genetic abnormalities associated with acute myeloid leukemia. This translocation generates the AML1-ETO fusion protein between the wild-type RUNX1 transcription factor and wild-type ETO transcriptional corepressor. To better understand the role of HDAC3 in t(8;21) leukemogenesis, the human HDAC3-containing complexes were isolated from stably-transfected HeLa cells by using anti-FLAG immunoprecipitation. The resulting complexes were resolved in SDS-PAGE. The components of the complexes were identified using LC-MS/MS. We report here that the human RUNX1 transcription is a component of the HDAC3 complexes. We demonstrate that HDAC3 and RUNX1 collaboratively repress AML1-ETO-mediated transcription. These results reveal new insight into how AML1-ETO, RUNX1, and HDAC3 crosstalk to deregulate gene transcription in t(8;21) leukemia cells.
2020-02-17 | PXD017230 | Pride
Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
2023-05-10 | PXD030616 | Pride
Project description:Identification of RUNX1 and ETV6-RUNX1 binding sites
2022-04-10 | E-MTAB-10312 | biostudies-arrayexpress
Project description:Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML.
2019-04-12 | GSE117107 | GEO
Project description:Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML.
2019-04-12 | GSE117105 | GEO
Project description:We prepared five RASF samples from each donor under four conditions: in the presence or absence of CDK4/6 inhibitor, palbociclib, and with or without cytokine stimulations. In total, 20 samples were analyzed. RASFs were treated with CDK4/6 inhibitor for 24 hours in advance to the stimulation. RNA was collected after 24 hours of the stimulation(TNF+IL-1b, 0.2ng/ml each)
2023-01-26 | E-MTAB-10795 | biostudies-arrayexpress
Project description:ETV6-RUNX1 is a first-hit mutation in childhood B cell precursor acute lymphoblastic leukaemia. ETV6-RUNX1 is a fusion protein which inherits the DNA-binding runt domain from RUNX1. Here we performed chromatin precipitation for native RUNX1 and ETV6-RUNX1 using RUNX1 antibodies and specifically for the ETV6-RUNX1 fusion using a V5-tag pull down.
2022-10-31 | E-MTAB-12208 | biostudies-arrayexpress