E2/Estrogen receptor/sjogren syndrome-associated autoantigen relieves coactivator activator-induced G1/S arrest to promote breast tumorigenicity

Mol Cell Biol. 2014 May;34(9):1670-81. doi: 10.1128/MCB.01564-13. Epub 2014 Feb 24.

Abstract

Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G(1)/S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.

Publication types

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

MeSH terms

  • Breast / immunology
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Carcinogenesis / pathology
  • Cell Cycle Checkpoints
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, myc*
  • Humans
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Proteolysis
  • Receptors, Estrogen / immunology*
  • Ribonucleoproteins / immunology*
  • Ubiquitin-Conjugating Enzymes / immunology
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitination

Substances

  • Intracellular Signaling Peptides and Proteins
  • RBM14 protein, human
  • Receptors, Estrogen
  • Ribonucleoproteins
  • SS-A antigen
  • Ubiquitin-Conjugating Enzymes