The promyelocytic leukemia protein isoform PML1 is an oncoprotein and a direct target of the antioxidant sulforaphane (SFN)

Biochim Biophys Acta Mol Cell Res. 2020 Aug;1867(8):118707. doi: 10.1016/j.bbamcr.2020.118707. Epub 2020 Mar 31.


The gene encoding promyelocytic leukemia protein (PML) generates several spliced isoforms. Ectopic expression of PML1 promotes the proliferation of ERα-positive MCF-7 breast cancer (BC) cells, while a loss of PML by knockdown or overexpression of PML4 does the opposite. PML is an essential constituent of highly dynamic particles called PML nuclear bodies (NBs). PML NBs are heterogenous multiprotein subnuclear structures that are part of cellular stress sensing machinery. The antioxidant sulforaphane (SFN) inhibits the proliferation of BC cells and causes a redistribution of the subcellular localization of PML, a disruption of disulfide-bond linkages in nuclear PML-containing complexes, and a reduction in the number and size of PML NBs. Mechanistically, SFN modifies several cysteine residues, including C204, located in the RBCC domain of PML. PML is sumoylated and contains a Sumo-interacting motif, and a significant fraction of Sumo1 and Sumo2/3 co-localizes with PML NBs. Ectopic expression of the mutant C204A selectively inhibits the biogenesis of endogenous PML NBs but not PML-less Sumo1-, Sumo2/3, or Daxx-containing nuclear speckles. Importantly, PML1 (C204A) functions as a dominant-negative mutant over endogenous PML protein and promotes anti-proliferation activity. Together, we conclude that SFN elicits its cytotoxic activity in part by inactivating PML1's pro-tumorigenic activity.

Keywords: Antioxidants; Disulfide bond linkages; PML nuclear bodies (NBs); Promyelocytic leukemia protein (PML); Sulforaphane.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antioxidants / metabolism*
  • Cell Cycle
  • Cell Movement
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Co-Repressor Proteins
  • Humans
  • Isothiocyanates / pharmacology*
  • MCF-7 Cells
  • Molecular Chaperones
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Promyelocytic Leukemia Protein / genetics*
  • Promyelocytic Leukemia Protein / metabolism*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • SUMO-1 Protein / metabolism
  • Small Ubiquitin-Related Modifier Proteins
  • Sulfoxides
  • Sumoylation
  • Ubiquitins / metabolism


  • Antioxidants
  • Co-Repressor Proteins
  • DAXX protein, human
  • Isothiocyanates
  • Molecular Chaperones
  • Oncogene Proteins
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • SUMO-1 Protein
  • SUMO1 protein, human
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Sulfoxides
  • Ubiquitins
  • PML protein, human
  • sulforaphane