Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 33, Pages 11707-11719Publisher
ELSEVIER
DOI: 10.1074/jbc.RA120.014018
Keywords
breast cancer; metastasis; invasion; transcription; alternative splicing; B-cell leukemia; lymphoma 11A (BCL11A); muscleblind-like splicing regulator 1 (MBNL1); integrin-alpha 6 (ITGA6); gene regulation; gene transcription
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Funding
- Department of Defense [W81XWH-14-1-0354]
- NIH [R01 CA206505]
- Clinical and Translational Science Collaborative of Cleveland [KL2 TR000440]
- University Hospitals Department of Medicine Team Science Award 2014
- Genomics Core Facility of the CWRU School of Medicine's Genetics and Genome Sciences Department
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The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-alpha 6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing ofITGA6. Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.
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