期刊
ONCOTARGET
卷 7, 期 15, 页码 19134-19146出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8102
关键词
BAF180; cellular senescence; hematopoietic stem cell; p21; Gerotarget
资金
- UT MD Anderson Cancer Center
- Cancer Prevention & Research Institute of Texas [RP130020]
- National Institutes of Health [CA181196, CA190370]
- Ellison Medical Foundation [AG-NS-0973-13]
- Gabrielle's Angel Foundation for Cancer Research
- NIH/NCI [CA164346]
- CPRIT [RP140402]
- Center for Genetics and Genomics, Center for Inflammation and Cancer, Institutional Research Grant
- Sister Institution Network fund of UT MD Anderson Cancer Center
- National Institutes of Health Core Grant [CA016672]
BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology.
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