The PLOD2/succinate axis in cancer cell plasticity and stemness

PLOD2/琥珀酸轴在癌细胞可塑性和干细胞性中的作用

• 批准号: 10680932
• 负责人: Ren Xu
• 金额: $ 36.57万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680932
• 关键词: Aftercare; Biochemistry; Biological; Biometry; Breast; Breast Cancer Cell; Breast Epithelial Cells; Breast cancer metastasis; Cell Membrane Permeability; Cell physiology; Cells; ChIP-seq; Chromatin; Citric Acid Cycle; Clinical; Collagen; CpG Islands; Cytoplasm; DDR1 gene; DNA; Development; Dioxygenases; Endoplasmic Reticulum; Enzymes; Epigenetic Process; Exhibits; FDA approved; Fibroblasts; Fibrosis; Gene Expression Profiling; Genetic Transcription; Human; Hydroxylation; In Vitro; Incidence; Knockout Mice; Knowledge; Loperamide; Lysine; Malignant Neoplasms; Mediating; Mesenchymal; Metabolic; Modeling; Modification; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Pathologist; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Procollagen; Prognosis; Regulation; Relapse; Repression; Research; Role; Scheme; Succinates; TP53 gene; Testing; Tissue Sample; Tissues; Weight; Xenograft Model; alpha ketoglutarate; breast cancer progression; cancer cell; cancer subtypes; cell growth regulation; conditional knockout; crosslink; epigenetic regulation; epithelial to mesenchymal transition; experimental study; gain of function; inhibitor; loss of function; malignant breast neoplasm; metabolomics; mid-career faculty; mouse model; multidisciplinary; neoplastic cell; novel; patient derived xenograft model; screening; small hairpin RNA; stable isotope; stemness; therapeutic target; transcription factor; transcriptome sequencing; triple-negative invasive breast carcinoma

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.

摘要