Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Abstract

Sarcomas are uncommon but diverse mesenchymal malignancies arising from connective tissues, such as muscle, fat and cartilage. Despite rapid advances in molecular understanding of individual subtypes and pathway-specific therapies, the remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STS) limits clinical benefit of targeted treatments. A variety of metabolism-associated oncogenic signaling pathways have been identified in sarcomas. Both these internal and external alterations converge to change cell metabolism, rendering sarcoma cells more susceptible to perturbations within metabolic networks. However, how abnormal metabolism influences sarcoma growth remains understudied. I show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of STS subtypes, revealing an apparent common metabolic feature shared by diverse STS. Enforced FBP2 re-expression inhibits STS 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 (NRF1) 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 STS, identifying a potential metabolic vulnerability and possible future therapeutic target.

FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome

“…2f , g ). FBP2, another FBP family member, directly binds to MYC and inhibits its transcriptional activity in soft tissue sarcoma 46 , suggesting that MYC could impact certain metabolic genes in this context. Since Fbp1 is initially upregulated and subsequently silenced during NAFLD-HCC progression ( Fig.…”

Fructose 1,6-Bisphosphatase 2 Plays a Crucial Role in the Induction and Maintenance of Long-Term Potentiation

“…Fbp2 protects mitochondria against the effects of stress stimuli such as elevated calcium levels resulting in mitochondrial swelling and decreased ATP synthesis [ 7 ]. Fbp2 also undergoes cytoplasmic–nuclear shuttling in hormone-dependent manners [ 9 ], and it has been recently demonstrated that nuclear Fbp2 regulates mitochondrial biogenesis via interaction with c-Myc [ 10 ].…”

Expression of Fbp2, a Newly Discovered Constituent of Memory Formation Mechanisms, Is Regulated by Astrocyte–Neuron Crosstalk

“…Nuclear Fbp2 was shown to affect c-Myc-dependent mitochondria biogenesis and transcription of oxidative metabolism proteins [ 3 ]. Thus, the withdrawal of Fbp2 from astrocytic nuclei seems to be a part of the metabolic reprogramming of astrocytes preparing them, on the one hand, to intensified production of lactate in glycolysis and, on the other hand, to neuron-released glutamate turnover [ 23 ] in which mitochondria play a crucial role.…”

“…However, it plays also a variety of non-enzymatic functions. Fbp2 is involved in the regulation of hypoxia-inducible factor 1α (Hif1α) stability, cell cycle-dependent events, biogenesis of mitochondria, and protection of the organelles against high reactive oxygen species (ROS)- and high Ca 2+ -induced stress [ 1 , 2 , 3 , 4 ]. This diversity of functions results from the ability of Fbp2 to adopt different oligomeric forms in solution, from monomeric to octameric.…”