Different p53 Genotypes Regulate PPARγ Post-Translational Modification in The Adipogenic Differentiation of Cancer Cells

Background: Our previous studies confirmed that high concentrations of cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs). PGCCs have the properties of cancer stem cell. In this study, we demonstrate that PGCCs can be induced to differentiate into adipose in vitro and in vivo. In addition, the molecular mechanism of adipogenic differentiation of PGCCs with daughter cells was investigated by detecting the expression of adipocyte differentiation related proteins in mutant and wild-type p53 cancer cell lines. Methods: HEY and MDA-MB-231 control cells and PGCCs with daughter cells were cultured with adipogenic differentiation medium and the cell cycle was detected by flow cytometry. The expression of adipocyte differentiation related proteins, and P300 histone acetyltransferase activity were compared before and after adipogenic differentiation. Immunoprecipitation was used to analyze the post-translational modification of peroxisome proliferator-activator receptor-γ (PPARγ) and P53 in HEY and MDA-MB-231 control cells and PGCCs with daughter cells cultured with adipogenic differentiation medium. Animal xenograft models were used to study the adipogenic differentiation of PGCCs with daughter cells.Results: Dexamethasone, rosiglitazone, insulin, and 3-isobutyl-1-methylxanthine (IBMX) can force the trans-differentiation of PGCCs into post-mitotic and functional adipocytes. Activation of PPARγ is a critical step in the process of adipogenic differentiation. The expression levels of p-CREBser133, PPARγ, C/EBPα, C/EBPβ were higher in PGCCs with daughter cells after adipogenic differentiation compared with those without adipogenic differentiation in HEY and MDA-MB-231. P53 regulates the acetylation and phosphorylation of PPARγ and the expression of P300- Acetyl-PPARγ(Lys)- FABP4 and ERK- Phospho-PPARγ (Ser112)-FABP4 depended upon the genotype of p53 in HEY and MDA-MB-231 cells after cultured with adipogenic differentiation medium. The invasion and migration abilities of PGCCs with their daughter cells after adipogenic differentiation decreased compared with those cells without adipogenic differentiation.Conclusion: P300-P53-ERK-CREB-PPARγ-CEBPα/β-FABP4 pathway may participate in the adipogenic differentiation of HEY, MDA-MB-231 PGCCs with daughter cells, which associated with genotype of p53.

[1]  Minying Zheng,et al.  Molecular Mechanism of Stem Cell Differentiation into Adipocytes and Adipocyte Differentiation of Malignant Tumor , 2020, Stem cells international.

[2]  Minying Zheng,et al.  Different p53 genotypes regulating different phosphorylation sites and subcellular location of CDC25C associated with the formation of polyploid giant cancer cells , 2020, Journal of Experimental & Clinical Cancer Research.

[3]  B. Le Foll,et al.  Therapeutic Potential of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Substance Use Disorders: A Synthesis of Preclinical and Human Evidence , 2020, Cells.

[4]  F. Tacke,et al.  Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. , 2020, Journal of hepatology.

[5]  Shiwu Zhang,et al.  Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer , 2020, Frontiers in Oncology.

[6]  P. Bai,et al.  The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism , 2020, Genes & development.

[7]  M. Miyazaki,et al.  All-trans retinoic acid reduces the transcriptional regulation of intestinal sodium-dependent phosphate co-transporter gene (Npt2b). , 2020, The Biochemical journal.

[8]  D. Ménard,et al.  DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites , 2019, ACS central science.

[9]  F. Dantzer,et al.  Therapeutic considerations of PARP in stem cell biology: relevance in cancer and beyond. , 2019, Biochemical pharmacology.

[10]  Xipeng Zhang,et al.  Formation of Polyploid Giant Cancer Cells Involves in the Prognostic Value of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer , 2019, Journal of oncology.

[11]  Yoon-La Choi,et al.  Adipogenesis induces growth inhibition of dedifferentiated liposarcoma , 2019, Cancer science.

[12]  G. Christofori,et al.  Gain Fat-Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis. , 2019, Cancer cell.

[13]  Geoffrey I. Webb,et al.  Large-scale comparative assessment of computational predictors for lysine post-translational modification sites , 2018, Briefings Bioinform..

[14]  Sarah A. Clark,et al.  Multivalency regulates activity in an intrinsically disordered transcription factor , 2018, eLife.

[15]  Chunaram Choudhary,et al.  Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours , 2017, Nature.

[16]  L. Leibovici,et al.  Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis , 2014 .

[17]  Baocun Sun,et al.  Generation of cancer stem-like cells through the formation of polyploid giant cancer cells , 2014, Oncogene.

[18]  F. Holstege,et al.  Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60 , 2013, Nature Communications.

[19]  X. Sun,et al.  Stemness and inducing differentiation of small cell lung cancer NCI-H446 cells , 2013, Cell Death and Disease.

[20]  M. Lane,et al.  Adipogenesis: from stem cell to adipocyte. , 2012, Annual review of biochemistry.

[21]  T. Giordano,et al.  Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma. , 2011, Endocrinology.

[22]  T. Mäkelä,et al.  Mat1 Inhibits Peroxisome Proliferator-Activated Receptor γ-Mediated Adipocyte Differentiation , 2008, Molecular and Cellular Biology.

[23]  R. Seger,et al.  Interaction with MEK Causes Nuclear Export and Downregulation of Peroxisome Proliferator-Activated Receptor γ , 2006, Molecular and Cellular Biology.

[24]  F. Spener,et al.  Adipocyte-type fatty acid-binding protein as inter-compartmental shuttle for peroxisome proliferator activated receptor gamma agonists in cultured cell. , 2006, Biochimica et biophysica acta.

[25]  Chenguang Wang,et al.  Acetylation of nuclear receptors in cellular growth and apoptosis. , 2004, Biochemical pharmacology.

[26]  R. Roeder,et al.  Regulation of the p300 HAT domain via a novel activation loop , 2004, Nature Structural &Molecular Biology.

[27]  N. Perkins,et al.  DNA-dependent Acetylation of p53 by the Transcription Coactivator p300* , 2003, The Journal of Biological Chemistry.

[28]  L. Fajas.  Adipogenesis: a cross-talk between cell proliferation and cell differentiation , 2003, Annals of medicine.

[29]  K. Kristiansen,et al.  The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation. , 2002, Developmental cell.

[30]  Jie Zhou,et al.  Acetylation-defective mutant of Pparγ is associated with decreased lipid synthesis in breast cancer cells , 2018 .

[31]  K. Kristiansen,et al.  The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function. , 2009, Expert opinion on therapeutic targets.

[32]  Michael Lehrke,et al.  The many faces of PPARgamma. , 2005, Cell.

[33]  Béatrice Desvergne,et al.  Peroxisome-proliferator-activated receptors and cancers: complex stories , 2004, Nature Reviews Cancer.

[34]  T. King,et al.  Role of p53 and p16 gene alterations in determining response to concurrent paclitaxel and radiation in solid tumor. , 1999, Seminars in radiation oncology.

[35]  R A Graves,et al.  Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. , 1994, Nucleic acids research.