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Published on: March 26, 2018
SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute
Shankha Subhra Chatterjee1, Mayukh Biswas1, Liberalis Debraj Boila1
1Stem Cell & Leukemia Lab, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Translational Research Unit of Excellence (TRUE), Salt Lake, Kolkata, West Bengal, India.
Abstract:
SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are altered in approximately 25% of human malignancies, evidences showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNFΔ SMARCC1 (BAF155), an intact core component of SWI/SNFΔ, colocalized with H3K27Ac to target oncogenic loci in primary AML cells. Interestingly, gene ontology (GO) term and pathway analysis suggested that SMARCC1 occupancy was enriched on genes regulating Rac GTPase activation, cell trafficking, and AML-associated transcriptional dysregulation. Transcriptome profiling revealed that expression of these genes is upregulated in primary AML blasts, and loss-of-function studies confirmed transcriptional regulation of Rac GTPase guanine nucleotide exchange factors (GEF) by SMARCB1. Mechanistically, loss of SMARCB1 increased recruitment of SWI/SNFΔ and associated histone acetyltransferases (HAT) to target loci, thereby promoting H3K27Ac and gene expression. Together, SMARCB1 deficiency induced GEFs for Rac GTPase activation and augmented AML cell migration and survival. Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNFΔ function in maintaining an oncogenic gene expression program in AML.Implications: Loss of SMARCB1 in AML associates with SWI/SNFΔ nucleation, which in turn promotes Rac GTPase GEF expression, Rac activation, migration, and survival of AML cells, highlighting SWI/SNFΔ downstream signaling as important molecular regulator in AML. Mol Cancer Res; 16(5); 791-804. ©2018 AACR.
Insights
Loss of SMARCB1 in acute myeloid leukemia (AML) promotes SWI/SNF complex changes, increasing Rac GTPase GEF expression, cell migration, and survival. This highlights SMARCB1
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- SWI/SNF complexes are crucial for chromatin remodeling and cellular identity.
- Alterations in SWI/SNF genes are common in human cancers, but their role in tumor-specific chromatin regulation is not fully understood.
- Acute myeloid leukemia (AML) is a cancer with frequent genetic alterations.
Purpose of the Study:
- To investigate the role of SWI/SNF complex alterations in acute myeloid leukemia (AML).
- To elucidate the functional consequences of SMARCB1 loss in AML pathogenesis.
- To identify the downstream targets and mechanisms regulated by SWI/SNF in AML.
Main Methods:
- Analysis of SWI/SNF complex composition in primary AML cells.
- Chromatin immunoprecipitation (ChIP) to assess SWI/SNF and H3K27Ac occupancy.
- Gene expression profiling (transcriptome analysis).
- Loss-of-function studies to determine the impact of SMARCB1 deficiency.
Main Results:
- Primary AML cells showed loss of SMARCB1 and SMARCD2, with SWI/SNF-SMARCC1 nucleation at oncogenic loci.
- SMARCC1 occupancy was enriched on genes involved in Rac GTPase activation and cell trafficking.
- Loss of SMARCB1 upregulated Rac GTPase guanine nucleotide exchange factors (GEFs), enhancing AML cell migration and survival.
- SMARCB1 deficiency promoted histone acetyltransferase (HAT) recruitment and H3K27Ac levels at target genes.
Conclusions:
- SMARCB1 loss in AML leads to SWI/SNF complex alterations and promotes an oncogenic gene expression program.
- The SWI/SNF complex, particularly in its altered state (SWI/SNFΔ), plays a role in maintaining AML cell migration and survival.
- SMARCB1 acts as a tumor suppressor in AML by regulating Rac GTPase signaling pathways.
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