Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Division of Genetics and Metabolism, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Biochemistry, and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Metab. 2020 Jan 7;31(1):174-188.e7. doi: 10.1016/j.cmet.2019.10.012. Epub 2019 Nov 21.
The remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STSs) limits the clinical benefit of targeted therapies. Here, we show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of sarcoma subtypes, revealing an apparent common metabolic feature shared by diverse STSs. Enforced FBP2 expression inhibits sarcoma cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect," thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic-activity-independent manner by inhibiting the expression of nuclear respiratory factor and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STSs, identifying a potential metabolic vulnerability of this malignancy and possible therapeutic target.
软组织肉瘤（STS）具有显著的细胞和遗传异质性，限制了靶向治疗的临床获益。在这里，我们表明，广泛的肉瘤亚型中果糖-1,6-二磷酸酶 2（FBP2）的表达被沉默，揭示了不同 STSs 之间明显的共同代谢特征。强制表达 FBP2 通过两种不同的机制抑制肉瘤细胞和肿瘤的生长。首先，胞质 FBP2 拮抗与“Warburg 效应”相关的升高的糖酵解，从而抑制肉瘤细胞增殖。其次，核定位的 FBP2 通过抑制核呼吸因子和线粒体转录因子 A（TFAM）的表达，以非催化活性依赖性方式抑制线粒体生物发生和呼吸。具体而言，核 FBP2 与 c-Myc 转录因子在 TFAM 基因座处共定位，并抑制 c-Myc 依赖性 TFAM 表达。FBP2 的这种独特的双重功能为其在 STS 中的选择性抑制提供了依据，确定了这种恶性肿瘤的潜在代谢脆弱性和可能的治疗靶点。
