Pygo2 associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion.

Abstract

Resent studies have identified Pygopus as a core component of the β-catenin/T-cell factor (TCF)/lymphoid-enhancing factor 1 (LEF) transcriptional activation complex required for the expression of canonical Wg/Wnt target genes in Drosophila. However, the biochemical involvement of mammalian Pygopus proteins in β-catenin/TCF/LEF gene activation remains controversial. In this study, we perform a series of molecular/biochemical experiments to demonstrate that Pygo2 associates with histone-modifying enzymatic complexes, specifically the MLL2 histone methyltransferase (HMT) and STAGA histone acetyltransferase (HAT) complexes, to facilitate their interaction with β-catenin and to augment Wnt1-induced, TCF/LEF-dependent transcriptional activation in breast cancer cells. We identify a critical domain in Pygo2 encompassing the first 47 amino acids that mediates its HMT/HAT interaction. We further demonstrate the importance of this domain in Pygo2's ability to transcriptionally activate both artificial and endogenous Wnt target genes and to expand breast cancer stem-like cells in culture. This work now links mechanistically Pygo2's role in histone modification to its enhancement of the Wnt-dependent transcriptional program and cancer stem-like cell expansion.

• Authors: Jiakun Chen, Qicong Luo, Yuanyang Yuan, Xiaoli Huang, Wangyu Cai, Chao Li, Tongzhen Wei, Ludi Zhang, Meng Yang, Qingfeng Liu, Guodong Ye, Xing Dai, Boan Li
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 30 Issue 24 Pg. 5621-35 (Dec 2010) ISSN: 1098-5549 [Electronic] United States
• PMID: 20937768 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA-Binding Proteins
• Histones
• Intracellular Signaling Peptides and Proteins
• KMT2D protein, human
• LEF1 protein, human
• Lymphoid Enhancer-Binding Factor 1
• MYC protein, human
• Neoplasm Proteins
• PYGO2 protein, human
• Proto-Oncogene Proteins c-myc
• WNT1 protein, human
• Wnt1 Protein
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Animals
• Breast Neoplasms (enzymology, genetics, pathology)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Histones (genetics, metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Lymphoid Enhancer-Binding Factor 1 (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Neoplastic Stem Cells (cytology, physiology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Interference
• Wnt1 Protein (genetics, metabolism)
• p300-CBP Transcription Factors (genetics, metabolism)