Abstract
The tumor suppressor p53 has critical roles in regulating lipid metabolism, but whether and how p53 regulates cardiolipin (CL) de novo biosynthesis is unknown. Here, we report that p53 physically interacts with histone deacetylase SIRT6 in vitro and in vivo, and this interaction increases following palmitic acid (PA) treatment. In response to PA, p53 and SIRT6 localize to chromatin in a p53-dependent manner. Chromatin p53 and SIRT6 bind the promoters of CDP-diacylglycerol synthase 1 and 2 (CDS1 and CDS2), two enzymes required to catalyze CL de novo biosynthesis. Here, SIRT6 serves as a co-activator of p53 and effectively recruits RNA polymerase II to the CDS1 and CDS2 promoters to enhance CL de novo biosynthesis. Our findings reveal a novel, cooperative model executed by p53 and SIRT6 to maintain lipid homeostasis.
Highlights
The tumor suppressor p53 is known as the “guardian of the genome” due to its role in maintaining normal cell growth and genomic stability via cell-cycle regulation and inducing apoptosis and DNA damage repair in response to cellular stress[1,2]
Sirtuin 6 (SIRT6) recruits RNA polymerase II to the CDS1 and CDS2 promoters to upregulate the expression of these enzymes that are key for CL de novo biosynthesis
We propose a model, whereby SIRT6 serves as a co-activator of p53 to regulate CL de novo biosynthesis (Fig. 6e)
Summary
Given that p53 and SIRT6 are involved in many aspects of cell metabolic regulation, we asked whether they both participate in lipid homeostasis. Treatment did not markedly change in SIRT6 siRNAtreated cells compared to the non-specific siRNA-treated cells (Fig. 3c, d) These data indicate that SIRT6 has no effect on the expression of p53 or its increase on chromatin. Similar results were found in LoVo cells (Fig. 4a–d) and human liver cancer HepG2 cells (Supplementary Fig. S2C) These data indicate that PA can induce expression of CL de novo biosynthesis-related genes. We detected p53 localization to the CDS1 promoter in HCT116 cells by chromatin immunoprecipitation, and found that its binding activity significantly increased following PA treatment (Fig. 5a). Sequential ChIP assay revealed the co-occupancy of p53 and SIRT6 on CDS1 and CDS2 promoters in HCT116 (Fig. 5g, h) and HepG2 (supplementary Fig. S2D, E) cells These data indicate that SIRT6 does not drive CDS1 and CDS2 gene expression when p53 is absent. These data suggest that SIRT6 may serve as a co-activator of p53 to regulate CL de novo biosynthesis in the context of unbalance of lipid metabolism
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