Dual roles for coactivator activator and its counterbalancing isoform coactivator modulator in human kidney cell tumorigenesis

Cancer Res. 2008 Oct 1;68(19):7887-96. doi: 10.1158/0008-5472.CAN-08-1734.

Abstract

Coactivator activator (CoAA) has been reported to be a coactivator that regulates steroid receptor-mediated transcription and alternative RNA splicing. Herein, we show that CoAA is a dual-function coregulator that inhibits G(1)-S transition in human kidney cells and suppresses anchorage-independent growth and xenograft tumor formation. Suppression occurs in part by down-regulating c-myc and its downstream effectors ccnd1 and skp2 and causing accumulation of p27/Kip1 protein. In this cellular setting, CoAA directly represses the proto-oncogene c-myc by recruiting HDAC3 protein and decreasing both the acetylation of histone H3 and the presence of RNA polymerase II on the c-myc promoter. Interestingly, a splicing isoform of CoAA, coactivator modulator (CoAM), antagonizes CoAA-induced G(1)-S transition and growth inhibition by negatively regulating the mRNA levels of the endogenous CoAA isoform. In addition, we found that expression of CoAA protein is significantly decreased in human renal cell carcinoma compared with normal kidney. Our study presents evidence that CoAA is a potential tumor suppressor in renal carcinoma and that CoAM is a counterbalancing splice isoform. This is, thus far, the only example of a nuclear receptor coregulator involved in suppression of kidney cancer and suggests potentially significant new roles for coregulators in renal cancer biology.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Cycle / genetics
  • Cell Line
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cyclin D1 / genetics
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor / physiology
  • Genes, myc
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Models, Biological
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Isoforms / physiology
  • S-Phase Kinase-Associated Proteins / genetics
  • Transplantation, Heterologous

Substances

  • Intracellular Signaling Peptides and Proteins
  • Protein Isoforms
  • RBM14 protein, human
  • S-Phase Kinase-Associated Proteins
  • Cyclin D1