PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage

  • Cancer Discov. 2019 Sep;9(9):1306-1323. doi: 10.1158/2159-8290.CD-18-0083.
Jinfang Zhang   #  1  2  3 ,  Yu-Ru Lee   #  4  5 ,  Fabin Dang   #  3 ,  Wenjian Gan  3  6 ,  Archita Venugopal Menon  4  5 ,  Jesse M Katon  3  4 ,  Chih-Hung Hsu  7  8  9 ,  John M Asara  10 ,  Priyanka Tibarewal  11  12 ,  Nicholas R Leslie  11 ,  Yang Shi  8  9 ,  Pier Paolo Pandolfi  13  5 ,  Wenyi Wei  14
Affiliations
  • 1. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China.
  • 2. Medical Research Institute, Wuhan University, Wuhan, P.R. China.
  • 3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 4. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, Massachusetts.
  • 5. Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 6. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
  • 7. Department of Public Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
  • 8. Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
  • 9. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
  • 10. Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • 11. Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt University, Edinburgh, United Kingdom.
  • 12. UCL Cancer Institute, University College London, London, United Kingdom.
  • 13. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, Massachusetts. [email protected] [email protected].
  • 14. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. [email protected] [email protected].
  • # Contributed equally.
PMID: 31217297 DOI: 10.1158/2159-8290.CD-18-0083
Abstract

The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K-AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, governing efficient repair of DSBs partly through dephosphorylation of γH2AX. Of note, inhibiting NSD2-mediated methylation of PTEN, either through expressing methylation-deficient PTEN mutants or through inhibiting NSD2, sensitizes Cancer cells to combinatorial treatment with a PI3K Inhibitor and DNA-damaging agents in both Cell Culture and in vivo xenograft models. Therefore, our study provides a novel molecular mechanism for PTEN regulation of DSB repair in a methylation- and protein phosphatase-dependent manner. SIGNIFICANCE: NSD2-mediated dimethylation of PTEN is recognized by the 53BP1 tudor domain to facilitate PTEN recruitment into DNA-damage sites, governing efficient repair of DNA DSBs. Importantly, inhibiting PTEN methylation sensitizes Cancer cells to combinatorial treatment with a PI3K Inhibitor combined with DNA-damaging agents in both Cell Culture and in vivo xenograft models.This article is highlighted in the In This Issue feature, p. 1143.

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