PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent.
Aberrant DNA methylation plays a critical role in the development and progression of cancer. Failure to demethylate and to consequently reactivate methylation-silenced genes in cancer contributes to chemotherapeutic resistance, yet the regulatory mechanisms of DNA demethylation in response to chemotherapeutic agents remain unclear. Here, we show that promyelocytic leukemia (PML) ... recruits ten-eleven translocation dioxygenase 2 (TET2) to regulate DNA modification and cell proliferation in response to chemotherapeutic agents. TET2 was required by multiple chemotherapeutic agents (such as doxorubicin) to prmote 5-hydroxymethylcytosine (5hmC) formation. Stable isotope labeling with amino acids in cell culture, followed by immunoprecipitation-mass spectrometry, identified potential binding partners of TET2, of which PML mostly enhanced 5hmC formation. PML physically bound to TET2 via the PML C-terminal domain and recruited TET2 to PML-positive nuclear bodies. This interaction was disrupted by the PML-RARA t(15;17) mutation, which stems from chromosomal translocation between DNA encoding the C-terminal domain of PML and the retinoic acid receptor alpha (RARA) gene. In response to chemotherapeutic drugs, PML recruited TET2, regulated DNA modification, reactivated methylation-silenced genes, and impaired cell proliferation. Knockout of PML abolished doxorubicin-promoted DNA modification. In addition, PML and TET2 levels positively correlated with improved overall survival in patients with head and neck cancer. These findings shed insight into the regulatory mechanisms of DNA modification in response to chemotherapeutic agents.Significance: Promyeloctic leukemia protein recruits TET2, regulating DNA modification and cell proliferation in response to chemotherapeutic agents. Cancer Res; 78(10); 2475-89. ©2018 AACR.
Mesh Terms:
5-Methylcytosine, Animals, Antineoplastic Agents, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Tumor, Cell Proliferation, DNA Methylation, DNA-Binding Proteins, Doxorubicin, Drug Resistance, Neoplasm, HEK293 Cells, Head and Neck Neoplasms, Humans, Leukemia, Promyelocytic, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Promyelocytic Leukemia Protein, Proto-Oncogene Proteins, RNA Interference, RNA, Small Interfering, Retinoic Acid Receptor alpha, Xenograft Model Antitumor Assays
5-Methylcytosine, Animals, Antineoplastic Agents, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Tumor, Cell Proliferation, DNA Methylation, DNA-Binding Proteins, Doxorubicin, Drug Resistance, Neoplasm, HEK293 Cells, Head and Neck Neoplasms, Humans, Leukemia, Promyelocytic, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Promyelocytic Leukemia Protein, Proto-Oncogene Proteins, RNA Interference, RNA, Small Interfering, Retinoic Acid Receptor alpha, Xenograft Model Antitumor Assays
Cancer Res.
Date: Dec. 15, 2017
PubMed ID: 29735542
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