Time-course transcriptomic profiling of cell-cycle entry in MCF10A cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE173509 | GEO | 2021/04/29
REPOSITORIES: GEO
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Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. DIPG has high percentage histone mutation at K27M on histone H3 locus, which is believed to be one of the drivers of the tumorigenesis. Dysregulation of G1/S cell cycle checkpoint is more enriched in the H3.3K27M mutant subgroup. In this study, we reported that palbociclib (PD0332991), a specific and cytostatic inhibitor of CDK4/6, effectively suppresses the growth of DIPG cells in vitro and in vivo. We established patient derived cell lines from treatment-naïve specimens, which all have H3.3K27M mutation. And our DIPG cell lines with H3.3K27M mutation have high CDK4/6 expression. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed all 8 cell lines self-renewal, proliferation and cell cycle progression from G1 to S phase in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as Myc. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Our findings revealed that palbociclib could be the therapy strategy for DIPG.
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Project description:Proteomic and phosphoproteomic analysis of MCF7 cells treated with Palbociclib (CDK4/6 inhibitor), PF3600 (CDK2 inhibitor) or both for 1 hour and 24 hours.
'P_1_1'
P refers to phosphoproteomic analysis. Otherwise, global proteomics was performed.
Number (1,2,3) refers to the run number. 3 runs were performed. Samples were TMT labelled and in each run there were the following samples:
DMSO 1 h, DMSO 24 h, 1uM Palbociclib 25nM PF3600 1 h, 1uM Palbociclib 25nM PF3600 24 h, 1uM Palbociclib 1 h, 1uM Palbociclib 24 h, 25nM PF3600 1 h, 25nM PF3600 24 h.
Number (1-24 for P or 1-12 for global) refers to the fraction.
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Project description:normal breast cell line MCF10A were treated with TSA or vehicle (DMSO) for 4 hours
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Project description:By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. Induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell cycle phases. S-phase synchronization upon removal of the early-G1 block (pG1-S) fails to completely restore scheduled gene expression. Consequently, coordinate loss of IRF4 and gain of Bim and Noxa expression sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 and more profoundly in pG1-S in vitro. Induction of pG1 and pG1-S by CDK4/CDK6 inhibition augments tumor-specific bortezomib killing in myeloma xenografts. Inhibition of CDK4/CDK6 in combination therapy thus represents a novel mechanism-based cancer therapy. PD 0332991 (PD) is the only known specific and reversible CDK4/CDK6 inhibitor. Gene expression was measured in myeloma MM1.S cells treated with PD (0.25 uM) in triplicate for 12, 24 or 36 h, or in cells released from G1, induced by 24hPD, for 4 or 18 h.
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Project description:Time-course transcriptomic profiling of cell-cycle entry in MCF10A cells
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Project description:MCF10A were either untreated, treated with torin or by starvation, to induce autophagy. RNA sequencing and ribosome profiling was performed.
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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) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Then we found that MITF is interacting with OGT in Palbociclib-resistance cells, and we also identified that Ser49 is the main O-GlcNAc site of MITF. O-GlcNAc of MITF is critical to mediated Palbociclib-resistance in cells.
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Project description:CDK4/6 inhibitors are used in the treatment of advanced estrogen receptor (ER)(+) breast cancer (BC). Their efficacy in ER(-) and early stage BC is currently under investigation. Here, we show that palbociclib, a CDK4/6 inhibitor, can inhibit both progression of ductal carcinoma in situ (DCIS) and growth of invasive disease in both an ER(-) basal BC model (MCFDCIS) and an ER(+) luminal model (MCF7 intraductal injection). In MCFDCIS cells palbociclib repressed cell cycle gene expression, inhibited proliferation, induced senescence and normalized tumorspheres formed in Matrigel whilst the formation of acini by normal mammary epithelial cells (MCF10A) was not affected. Palbociclib treatment of mice with MCFDCIS tumors inhibited their malignant progression and reduced proliferation of invasive lesions. Transcriptomic analysis of the tumor and stromal cell compartments showed that cell cycle and senescence genes, and MUC16, an ovarian cancer biomarker gene, were repressed during treatment. Knockdown of MUC16 in MCFDCIS cells inhibited proliferation of invasive lesions but not progression of DCIS. After cessation of palbociclib treatment genes associated with differentiation, e.g. p63, inflammation, IFNγ response and antigen processing and presentation remained suppressed in the tumor and surrounding stroma. We conclude that palbociclib can prevent progression of DCIS and is anti-proliferative in ER(-) invasive disease mediated in part via MUC16. Lasting effects of CDK4/6 inhibition after drug withdrawal on differentiation and the immune response could impact the approach to treatment of early stage ER(-) breast cancer.
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