A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism

Genes Dev. 2017 Oct 15;31(20):2056-2066. doi: 10.1101/gad.306092.117. Epub 2017 Nov 14.


Mutations and translocations within the COMPASS (complex of proteins associated with Set1) family of histone lysine methyltransferases are associated with a large number of human diseases, including cancer. Here we report that SET1B/COMPASS, which is essential for cell survival, surprisingly has a cytoplasmic variant. SET1B, but not its SET domain, is critical for maintaining cell viability, indicating a novel catalytic-independent role of SET1B/COMPASS. Loss of SET1B or its unique cytoplasmic-interacting protein, BOD1, leads to up-regulation of expression of numerous genes modulating fatty acid metabolism, including ADIPOR1 (adiponectin receptor 1), COX7C, SDC4, and COQ7 Our detailed molecular studies identify ADIPOR1 signaling, which is inactivated in both obesity and human cancers, as a key target of SET1B/COMPASS. Collectively, our study reveals a cytoplasmic function for a member of the COMPASS family, which could be harnessed for therapeutic regulation of signaling in human diseases, including cancer.

Keywords: chromatin; gene expression; transcription.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P-450 Enzyme System / physiology*
  • Cytoplasm / enzymology
  • Cytoplasm / metabolism
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histone-Lysine N-Methyltransferase / physiology*
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • PR-SET Domains
  • Protein Subunits / metabolism
  • Receptors, Adiponectin / metabolism
  • Signal Transduction
  • Triple Negative Breast Neoplasms / etiology
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology


  • ADIPOR1 protein, human
  • Bod1 protein, human
  • Cell Cycle Proteins
  • Protein Subunits
  • Receptors, Adiponectin
  • Cytochrome P-450 Enzyme System
  • Histone-Lysine N-Methyltransferase
  • SETD1B protein, human
  • Setd1A protein, human