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Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2
Ruijuan Xu1,2, Monica Garcia-Barros1,2, Sally Wen1,2
1Department of Medicine, State University of New York (SUNY), Stony Brook, NY, 11794, USA.
Abstract:
p53 mediates the DNA damage response (DDR) by regulating the expression of genes implicated in cell cycle arrest, senescence, programmed cell death (PCD), and metabolism. Herein we demonstrate that human alkaline ceramidase 2 (ACER2) is a novel transcriptional target of p53 and that its transactivation by p53 mediates the DDR. We found that p53 overexpression or its activation by ionizing radiation (IR) upregulated ACER2 in cells. Two putative p53 responsive elements (p53REs) were found in its first intron of the ACER2 gene, and Chromatin Immunoprecipitation (ChIP) assays in combination with promoter activity assays demonstrated that these p53REs are the bona fide p53 binding sites that mediate ACER2 transactivation by p53. As ACER2 catalyzes the hydrolysis of ceramides into sphingosine, which in turn is phosphorylated to form sphingosine-1-phosphate (S1P), ACER2 upregulation increased the levels of both sphingosine and S1P while decreasing the levels of ceramides in cells. A moderate upregulation of ACER2 inhibited cell cycle arrest and cellular senescence in response to low-level expression of p53 or low-dose IR by elevating S1P, a pro-proliferative and pro-survival bioactive lipid, and/or decreasing ceramides whereas its robust upregulation mediated PCD in response to high-level expression of p53 or high-dose IR likely by accumulating cellular sphingosine, a pro-death bioactive lipid. ACER2 is frequently inactivated in various cancers due to its deletion or mutations, and restoring its expression inhibited the growth of tumor xenografts in mice. These results suggest that p53 mediates DDR and exerts its tumor suppressive role in part by regulating the expression of ACER2, which in turn regulates the bioactive sphingolipid lipids.
Insights
The tumor suppressor p53 regulates the DNA damage response by controlling ACER2 gene expression. ACER2
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The p53 protein is a key regulator of the DNA damage response (DDR), controlling processes like cell cycle arrest, senescence, and programmed cell death (PCD).
- Bioactive lipids, such as ceramides and sphingolipids, play crucial roles in cellular signaling and fate.
- Dysregulation of ACER2 and its associated lipid pathways are implicated in cancer development.
Purpose of the Study:
- To identify novel transcriptional targets of p53 involved in the DDR.
- To elucidate the role of alkaline ceramidase 2 (ACER2) in p53-mediated DNA damage response.
- To investigate the impact of ACER2 on bioactive sphingolipid levels and cellular outcomes.
Main Methods:
- p53 overexpression and ionizing radiation (IR) treatments to induce DNA damage.
- Chromatin Immunoprecipitation (ChIP) and promoter activity assays to identify p53 binding sites.
- Measurement of ceramide, sphingosine, and sphingosine-1-phosphate (S1P) levels.
- Cell cycle arrest, senescence, and PCD assays.
Main Results:
- ACER2 is identified as a novel transcriptional target of p53.
- p53 directly binds to two p53-responsive elements (p53REs) in the ACER2 gene intron to mediate its transactivation.
- ACER2 upregulation alters sphingolipid metabolism, increasing sphingosine and S1P while decreasing ceramides.
- Moderate ACER2 upregulation promotes proliferation and survival by increasing S1P/decreasing ceramides.
- Robust ACER2 upregulation induces PCD by accumulating sphingosine.
- Restoring ACER2 expression inhibits tumor xenograft growth in mice.
Conclusions:
- p53 mediates the DNA damage response, in part, by regulating ACER2 expression.
- ACER2 acts as a critical node in the DDR, modulating cellular fate through sphingolipid metabolism.
- ACER2's tumor suppressive role highlights its potential as a therapeutic target in cancer.
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