Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 516080, China.
Neoplasia. 2019 Jan;21(1):61-73. doi: 10.1016/j.neo.2018.11.008. Epub 2018 Nov 30.
Protein kinase C (PKC) has critical roles in regulating lipid anabolism and catabolism. PKCζ, a member of atypical PKC family, has been reported to mediate glucose metabolism. However, whether and how PKCζ regulates tumor cells fatty acid β-oxidation are unknown. Here, we report that the phosphorylation of SIRT6 is significantly increased after palmitic acid (PA) treatment in colon cancer cells. PKCζ can physically interact with SIRT6 in vitro and in vivo, and this interaction enhances following PA treatment. Further experiments show that PKCζ is the phosphorylase of SIRT6 and phosphorylates SIRT6 at threonine 294 residue to promote SIRT6 enrichment on chromatin. In the functional study, we find that the expression of ACSL1, CPT1, CACT, and HADHB, the genes related to fatty acid β-oxidation, increases after PA stimulation. We further confirm that PKCζ mediates the binding of SIRT6 specifically to the promoters of fatty acid β-oxidation-related genes and elicits the expression of these genes through SIRT6 phosphorylation. Our findings demonstrate the mechanism of PKCζ as a new phosphorylase of SIRT6 on maintaining tumor fatty acid β-oxidation and define the new role of PKCζ in lipid homeostasis.
蛋白激酶 C（PKC）在调节脂质合成和分解代谢中具有关键作用。PKCζ，一种非典型 PKC 家族的成员，被报道可以介导葡萄糖代谢。然而，PKCζ 是否以及如何调节肿瘤细胞脂肪酸β-氧化尚不清楚。在这里，我们报告在结肠癌细胞中，棕榈酸（PA）处理后 SIRT6 的磷酸化明显增加。PKCζ 可以在体外和体内与 SIRT6 物理相互作用，并且这种相互作用在 PA 处理后增强。进一步的实验表明，PKCζ 是 SIRT6 的磷酸化酶，可将 SIRT6 磷酸化丝氨酸 294 残基，以促进 SIRT6 在染色质上的富集。在功能研究中，我们发现 ACSL1、CPT1、CACT 和 HADHB 的表达增加，这些基因与脂肪酸β-氧化有关，在 PA 刺激后增加。我们进一步证实，PKCζ 通过 SIRT6 磷酸化介导 SIRT6 特异性结合到脂肪酸β-氧化相关基因的启动子上，并引发这些基因的表达。我们的研究结果表明 PKCζ 作为 SIRT6 的一种新的磷酸化酶在维持肿瘤脂肪酸β-氧化中的机制，并定义了 PKCζ 在脂质平衡中的新作用。
