title: A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells.
abstract: The inactivation of p53 creates a major challenge for inducing apoptosis in cancer cells. An attractive strategy is to identify and subsequently target the survival signals in p53 defective cancer cells. Here we uncover a RUNX2-mediated survival signal in p53 defective cancer cells. The inhibition of this signal induces apoptosis in cancer cells but not non-transformed cells. Using the CRISPR technology, we demonstrate that p53 loss enhances the apoptosis caused by RUNX2 knockdown. Mechanistically, RUNX2 provides the survival signal partially through inducing MYC transcription. Cancer cells have high levels of activating histone marks on the MYC locus and concomitant high MYC expression. RUNX2 knockdown decreases the levels of these histone modifications and the recruitment of the Menin/MLL1 (mixed lineage leukemia 1) complex to the MYC locus. Two inhibitors of the Menin/MLL1 complex induce apoptosis in p53 defective cancer cells. Together, we identify a RUNX2-mediated epigenetic mechanism of the survival of p53 defective cancer cells and provide a proof-of-principle that the inhibition of this epigenetic axis is a promising strategy to kill p53 defective cancer cells.
authors.affiliation: Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Min Hwa
authors.initials: MH
authors.lastname: Shin
authors.affiliation: Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: He
authors.affiliation: Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Eryney
authors.initials: E
authors.lastname: Marrogi
authors.affiliation: Division of Pediatric Hematology-Oncology, The Children's Hospital at Montefiore, Bronx, New York, United States of America.
authors.forename: Sajida
authors.initials: S
authors.lastname: Piperdi
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Ren
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.affiliation: Division of Pediatric Hematology-Oncology, The Children's Hospital at Montefiore, Bronx, New York, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: Transgenic Core Facility, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D006801:Humans; D018345:Mice, Knockout; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C493692:CBFB protein, human; D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; C493709:RUNX2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53