MYC interaction with the tumor suppressive SWI/SNF complex member INI1 regulates transcription and cellular transformation.
MYC is a key driver of cellular transformation and is deregulated in most human cancers. Studies of MYC and its interactors have provided mechanistic insight into its role as a regulator of gene transcription. MYC has been previously linked to chromatin regulation through its interaction with INI1 (SMARCB1/hSNF5/BAF47), a core member of the SWI/SNF chromatin remodeling complex. INI1 is a potent tumor suppressor that is inactivated in several types of cancers, most prominently as the hallmark alteration in pediatric malignant rhabdoid tumors. However, the molecular and functional interaction of MYC and INI1 remains unclear. Here, we characterize the MYC-INI1 interaction in mammalian cells, mapping their minimal binding domains to functionally significant regions of MYC (leucine zipper) and INI1 (repeat motifs), and demonstrating that the interaction does not interfere with MYC-MAX interaction. Protein-protein interaction network analysis expands the MYC-INI1 interaction to the SWI/SNF complex and a larger network of chromatin regulatory complexes. Genome-wide analysis reveals that the DNA-binding regions and target genes of INI1 significantly overlap with those of MYC. In an INI1-deficient rhabdoid tumor system, we observe that with re-expression of INI1, MYC and INI1 bind to common target genes and have opposing effects on gene expression. Functionally, INI1 re-expression suppresses cell proliferation and MYC-potentiated transformation. Our findings thus establish the antagonistic roles of the INI1 and MYC transcriptional regulators in mediating cellular and oncogenic functions.
a Department of Medical Biophysics , Faculty of Medicine, University of Toronto , Toronto , Ontario , Canada.|b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Angelina
A
Stojanova
a Department of Medical Biophysics , Faculty of Medicine, University of Toronto , Toronto , Ontario , Canada.|b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
William B
WB
Tu
b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Romina
R
Ponzielli
b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Max
M
Kotlyar
b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Pak-Kei
PK
Chan
a Department of Medical Biophysics , Faculty of Medicine, University of Toronto , Toronto , Ontario , Canada.|b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.|c Informatics and Biocomputing Program, Ontario Institute for Cancer Research , Toronto , Ontario , Canada.
Paul C
PC
Boutros
b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Fereshteh
F
Khosravi
a Department of Medical Biophysics , Faculty of Medicine, University of Toronto , Toronto , Ontario , Canada.|b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.|d Department of Computer Science , University of Toronto , Toronto , Ontario , Canada.
Igor
I
Jurisica
a Department of Medical Biophysics , Faculty of Medicine, University of Toronto , Toronto , Ontario , Canada.|b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Brian
B
Raught
a Department of Medical Biophysics , Faculty of Medicine, University of Toronto , Toronto , Ontario , Canada.|b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada.
Linda Z
LZ
Penn
D020816:Amino Acid Motifs; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D042002:Chromatin Assembly and Disassembly; D017124:Conserved Sequence; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016350:Leucine Zippers; D011485:Protein Binding; D055503:Protein Multimerization; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D000071796:SMARCB1 Protein / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; D016271:Proto-Oncogene Proteins c-myc; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human
INI1/SMARCB1/hSNF5/BAF47; MAX; SWI/SNF complex/BAF complex; c-MYC; cellular transformation; chromatin regulatory complex; protein-protein interaction; rhabdoid tumors; transcriptional regulation