Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9.
Overexpression of mac25 in the prostate cancer cell line M12 effects a dramatic reversal of the transformed phenotype. cDNA array analysis of RNA from cells overproducing the mac25 protein (M12/mac25) indicated upregulation of the sex determining transcription factor SOX9. In this study, we have confirmed increased expression of SOX9 in M12/mac25 cells and have further investigated the physiological effects of increased SOX9 production. Greatly increased levels of SOX9 RNA and mature protein were demonstrated in cells transfected with a SOX9 cDNA (M12/SOX9), and gel mobility shift assays confirmed binding of nuclear protein from these cells to an oligonucleotide containing the SOX9 consensus binding sequence. M12/SOX9 cells assumed the spindle-shaped morphology characteristic of M12/mac25 cells, suggesting that SOX9 mediates some effects of mac25. Elevated expression of SOX9 resulted in a decreased rate of cellular proliferation, cell cycle arrest in G0/G1, and increased sensitivity to apoptosis. Tumor development in athymic nude mice was inhibited by 80%. Finally, prostate-specific antigen and the androgen receptor, two genes whose expression is characteristic of differentiated cells, were both upregulated in M12/SOX9 cells. These data indicate that SOX9 contributes to growth regulation by mac25 via inhibition of cell growth and promotion of differentiation.
Drivdahl
Rolf
R
Veterans Affairs Puget Sound Health Care System, Seattle, WA 98105, USA.
Haugk
Kathy H
KH
Sprenger
Cynthia C
CC
Nelson
Peter S
PS
Tennant
Marie K
MK
Plymate
Stephen R
SR
D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D015197:Carcinogenicity Tests; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics; D055758:SOX9 Transcription Factor; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D000951:Antigens, Neoplasm; D015415:Biomarkers; D058851:GPI-Linked Proteins; D006609:High Mobility Group Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; C504399:Psca protein, mouse; D011944:Receptors, Androgen; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; C102529:insulin-like growth factor binding protein-related protein 1; D017430:Prostate-Specific Antigen