Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells
Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells
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DOI：
10.1158/0008-5472.can-18-2070
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发表时间：
2019-07-01
期刊：
影响因子：
11.2
通讯作者：
Minchiotti, Gabriella
中科院分区：
文献类型：
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作者：
D'Aniello, Cristina;Cermola, Federica;Minchiotti, Gabriella
胶原蛋白脯氨酰羟化（CPH）是由脯氨酰4-羟化酶（P4 H）催化的，是人类最普遍的翻译后修饰，需要维生素C（VitC）。在这里，我们证明，CPH作为一个细胞可塑性的表观遗传调制器。CPH增加诱导多能干细胞和肿瘤细胞中的整体DNA/组蛋白甲基化，并促进细胞状态转换（CST）。通过基因切除P4 H α 2亚基（P4 HA 2）或药物治疗来干扰CPH，可逆转表观遗传变化并拮抗CST。从机制上讲，我们认为CPH通过减少DNA和组蛋白脱甲基酶的VitC来改变表观遗传景观。靶向CPH介导的代谢紊乱的药物，如抗哮喘的布地奈德，通过阻止间充质转化在体内阻断乳腺癌细胞的转移性传播。我们的研究提供了机制的见解如何代谢线索和表观遗传因素整合控制CST和铺平了道路，为发展新的抗转移strategies.Significance：基于表型的高通量筛选揭示了不可预见的细胞可塑性的代谢控制，并确定布地奈德作为转移性癌症的候选药物。
Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic budesonide, blocked metastatic dissemination of breast cancer cells in vivo by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies.Significance: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.