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Supplementary Data from Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

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posted on 2023-03-31, 02:26 authored by Cristina D'Aniello, Federica Cermola, Andrea Palamidessi, Luca G. Wanderlingh, Miriam Gagliardi, Agnese Migliaccio, Francesca Varrone, Laura Casalino, Maria R. Matarazzo, Dario De Cesare, Giorgio Scita, Eduardo J. Patriarca, Gabriella Minchiotti

Supplementary data include Figure S1(Structural determinants of ESC inhibitors), Figure S2 (Validation and functional characterization of esMTi), Figure S3 (Generation and characterization of P4H deficient ESCs), Figure S4 (Budesonide activity on A549 lung tumor cells ); Figure S5 (Budesonide activity on SUM159 cells); Table S1 (The primer sequences and application); Table S2 (The Primary Antibodies and application); Table S3 (List of all ESC inhibitors), Table S4 (ESC inhibitors with anti-cancer activity and related references); Table S5 (List of esMT inhibitors), Table S6 (esMT inhibitors with anti-collagen/fibortic effects)

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ARTICLE ABSTRACT

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. A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.

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    Cancer Research

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    Breast CancerProgression, Invasion & MetastasisCell adhesion and extracellular matrixMigration and invasionStem Cell Biology

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