Abstract
Recent advances in tumor metabolism have revealed that metabolic reprogramming could dramatically promote caner metastasis. However, the relation and mechanism between metastasis and metabolic reprogramming are not thoroughly explored. Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of FAM210B in human cancer cells. Human ovarian cancer xenograft model was used to determine the effects of inhibiting FAM210B by shRNA on tumor metastasis. Microarray analysis was used to determine the target genes of FAM210B. FAM210B cellular localization was performed by mitochondria isolation and mitochondria protein extraction. To detect FAM210B-mediated metabolic reprogramming, oxygen consumption rate and extracellular acidification rate were measured. Our previous study screened a novel cancer progression-suppressor gene, FAM210B, which encodes an outer mitochondrial membrane protein, by the suppression of mortality by antisense rescue technique (SMART). Here we demonstrated that FAM210B loss was significantly associated with cancer metastasis and decreased survival in a clinical setting. Additionally, it was found that low expression of FAM210B was significantly correlated with decreased survival and enhanced metastasis in vivo and in vitro, and the loss of FAM210B led to an increased mitochondrial respiratory capacity and reduced glycolysis through the downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which activated the EMT program and enhanced migratory and invasive properties. Collectively, our data unveil a potential metabolic target and mechanism of cancer metastasis.
Highlights
An emerging hallmark of cancer is the reprogramming of energy metabolism to fuel tumor cell growth, division, and survival.[4,5,6] Recent studies have revealed that enhanced mitochondrial function have important roles in tumor proliferation and metastasis.[7,8,9,10] The metabolic status malignant tumors exploit to regulate growth and proliferation is becoming increasingly clear.[11]
Our previous study screened the novel gene FAM210B from the library involved in the tumor-selective killing of trichostatin A (TSA) by suppression of mortality by antisense rescue technique (SMART).[12]
We showed that low expression of the new gene FAM210B attenuated the TSA effects in cancer cells and promoted malignant metastasis inhibition activated TGF-β signaling and subsequent EMTassociated gene expression
Summary
An emerging hallmark of cancer is the reprogramming of energy metabolism to fuel tumor cell growth, division, and survival.[4,5,6] Recent studies have revealed that enhanced mitochondrial function have important roles in tumor proliferation and metastasis.[7,8,9,10] The metabolic status malignant tumors exploit to regulate growth and proliferation is becoming increasingly clear.[11]. Our previous study screened the novel gene FAM210B from the library involved in the tumor-selective killing of trichostatin A (TSA) by suppression of mortality by antisense rescue technique (SMART).[12] In this study, further analysis indicated that FAM210B was a novel mitochondria outer membrane protein and low expression of FAM210B obviously promoted malignant metastasis in vitro and in vivo. Depletion of FAM210B in ovarian cancer cells displayed elevated mitochondrial respiration and decreased glycolysis relative to control cells via the suppression of its downstream target, pyruvate dehydrogenase kinase 4 (PDK4). Our results suggested that low expression of FAM210B promoted metastasis through metabolic reprogramming
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