The PLOD2/succinate axis in cancer cell plasticity and stemness

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Abstract Tumor cells in TNBC tissue exhibit enhanced cell plasticity and stemness, which is crucial for cancer metastasis. Metabolic and epigenetic reprogramming plays crucial roles in the regulation of cell plasticity. Succinate is an intermediate metabolite of the tricarboxylic acid (TCA) cycle. Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in breast cancer development and progression have not been well investigated. We showed that the epithelial-to-mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate. Importantly, treatment with the membrane permeable succinate was sufficient to induce mesenchymal phenotypes, enhance cancer cell stemness and colonization, and reduce DNA hydroxymethylation and gene transcription in mammary epithelial cells. Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) catalyzes lysine hydroxylation in endoplasmic reticulum and generates succinate as another product. We found that PLOD2 expression was induced in cancer cells in TNBC tissue, and increased PLOD2 expression correlates with poor prognosis and high chances of cancer metastasis. Silence of PLOD2 in cancer cells significant reduced cancer cell colonization and metastasis. PLOD2 expression was induced during EMT and associated with elevation of cytoplasmic succinate levels. Using gain- and loss-of function approaches, we showed that increased PLOD2 expression is necessary and sufficient to enhance the accumulation of cytoplasmic succinate. Importantly, silencing PLOD2 in breast cancer cells inhibited cancer cell stemness. The overall objective of this project is to define roles of the PLOD2/succinate axis in regulating cancer cell plasticity and stemness, and to evaluate biological activity of the new PLOD2 inhibitor in suppressing TNBC progression and metastasis. The central hypothesis of this proposal is that PLOD2-induced succinate accumulation enhances cancer cell plasticity and metastasis by reducing DNA hydroxymethylation; therefore, targeting the PLOD2/succinate axis is a potential strategy to halt TNBC progression and metastasis. To test this hypothesis, we propose the following aims: Aim 1. Elucidate the molecular and cellular mechanisms by which succinate enhances cancer cell plasticity and stemness. Aim 2. Define roles of the PLOD2/succinate axis in regulating breast cancer progression. Aim 3. Evaluate the potential of targeting PLOD2 to suppress breast cancer metastasis. Successfully completion of the project will reveal novel function of collagen hydroxylation enzymes in regulating succinate-associated epigenetic reprogramming and identify PLOD2 as a potential therapeutic target to suppress breast cancer metastasis.