A phosphatidylinositol 3-kinase-Pax3 axis regulates Brn-2 expression in melanoma.

Abstract

Deregulation of transcription arising from mutations in key signaling pathways is a hallmark of cancer. In melanoma, the most aggressive and lethal form of skin cancer, the Brn-2 transcription factor (POU3F2) regulates proliferation and invasiveness and lies downstream from mitogen-activated protein kinase (MAPK) and Wnt/β-catenin, two melanoma-associated signaling pathways. In vivo Brn-2 represses expression of the microphthalmia-associated transcription factor, MITF, to drive cells to a more stem cell-like and invasive phenotype. Given the key role of Brn-2 in regulating melanoma biology, understanding the signaling pathways that drive Brn-2 expression is an important issue. Here, we show that inhibition of phosphatidylinositol 3-kinase (PI3K) signaling reduces invasiveness of melanoma cells in culture and strongly inhibits Brn-2 expression. Pax3, a transcription factor regulating melanocyte lineage-specific genes, directly binds and regulates the Brn-2 promoter, and Pax3 expression is also decreased upon PI3K inhibition. Collectively, our results highlight a crucial role for PI3K in regulating Brn-2 and Pax3 expression, reveal a mechanism by which PI3K can regulate invasiveness, and imply that PI3K signaling is a key determinant of melanoma subpopulation diversity. Together with our previous work, the results presented here now place Brn-2 downstream of three melanoma-associated signaling pathways.

• Authors: Elise Bonvin, Paola Falletta, Heather Shaw, Veronique Delmas, Colin R Goding
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 32 Issue 22 Pg. 4674-83 (Nov 2012) ISSN: 1098-5549 [Electronic] United States
• PMID: 22988297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• PAX3 Transcription Factor
• PAX3 protein, human
• POU Domain Factors
• Paired Box Transcription Factors
• Phosphoinositide-3 Kinase Inhibitors
• Wnt Proteins
• transcription factor Brn-2
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Melanoma (genetics, metabolism, pathology)
• Mice
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Neoplasm Invasiveness
• PAX3 Transcription Factor
• POU Domain Factors (genetics, metabolism)
• Paired Box Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Promoter Regions, Genetic
• Protein Binding
• Signal Transduction (genetics)
• Skin Neoplasms (genetics, metabolism, pathology)
• Transcription, Genetic
• Wnt Proteins (genetics, metabolism)