XIAP-associating factor 1, a transcriptional target of BRD7, contributes to endothelial cell senescence
Jong-Ik Heo1, Wonwoo Kim2, Kyu Jin Choi1
1Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Abstract:
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is well known as an antagonist of XIAP-mediated caspase inhibition. Although XAF1 serves as a tumor-suppressor gene, the role of XAF1 in cellular senescence remains unclear. We found that XAF1 expression was increased by genotoxic agents, such as doxorubicin and ionizing radiation in pulmonary microvascular endothelial cells, consequently leading to premature senescence. Conversely, downregulation of XAF1 in premature senescent cells partially overcame endothelial cell senescence. p53 knockdown, but not p16 knockdown, abolished senescence phenotypes caused by XAF1 induction. XAF1 expression was transcriptionally regulated by Bromodomain 7 (BRD7). XAF1 induction with interferon-gamma (IFN-γ) treatment was abrogated by BRD7 knockdown, which resulted in blocking interferon-induced senescence. In lung cancer cells, XAF1 tumor suppressor activity was decreased by BRD7 knockdown, and inhibition of tumor growth by IFN-γ did not appear in BRD7-depleted xenograft tumors. These data suggest that XAF1 is involved in BRD7-associated senescence and plays an important role in the regulation of endothelial senescence through a p53-dependent pathway. Furthermore, regulation of the BRD7/XAF1 system might contribute to tissue or organismal aging and protection against cellular transformation.
Insights
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) promotes premature cellular senescence via a p53-dependent pathway. Its regulation by Bromodomain 7 (BRD7) impacts endothelial senescence and tumor suppression.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) antagonizes XIAP-mediated caspase inhibition and functions as a tumor suppressor.
- The specific role of XAF1 in cellular senescence, particularly in endothelial cells, remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of XAF1 in cellular senescence.
- To elucidate the regulatory mechanisms and pathways involving XAF1 in senescence and tumor suppression.
Main Methods:
- Treatment of pulmonary microvascular endothelial cells with genotoxic agents (doxorubicin, ionizing radiation) and interferon-gamma (IFN-γ).
- Manipulation of XAF1 and Bromodomain 7 (BRD7) expression via knockdown techniques.
- Assessment of senescence phenotypes, including p53 and p16 pathways.
- Evaluation of XAF1's tumor suppressor activity in lung cancer cells and xenograft models.
Main Results:
- Genotoxic agents and IFN-γ increased XAF1 expression, inducing premature senescence in endothelial cells.
- Downregulation of XAF1 partially reversed endothelial cell senescence.
- XAF1-induced senescence was dependent on p53 but not p16.
- BRD7 transcriptionally regulated XAF1, and BRD7 knockdown abrogated IFN-γ-induced senescence.
- BRD7 knockdown reduced XAF1's tumor suppressor activity and impaired IFN-γ's anti-tumor effects in vivo.
Conclusions:
- XAF1 is involved in BRD7-associated senescence and regulates endothelial senescence through a p53-dependent pathway.
- The BRD7/XAF1 system plays a significant role in cellular aging and potentially in cancer prevention.
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