Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/β-Catenin Signaling

Umaru, Banlanjo Abdulaziz; Kagawa, Yoshiteru; Shil, Subrata Kumar; Arakawa, Naoki; Pan, Yijun; Miyazaki, Hirofumi; Kobayashi, Shuhei; Yang, Shuhan; Cheng, An; Wang, Yifei; Shinoda, Yasuharu; Kiniwa, Yukiko; Okuyama, Ryuhei; Fukunaga, Kohji; Owada, Yuji

doi:10.1007/s11095-021-03009-9

Cited by 17 publications

(21 citation statements)

References 41 publications

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“…In fact, our work firstly reports the pro-metastatic function of FABP7 in NSCLC. Intriguingly, Umaru et al have found that FABP7 can foster proliferation in melanoma [ 55 ], but FABP7 did not display the same effect in NSCLC ( Figure S5 ), suggesting cancer context-dependent functions of FABP7. Moreover, Umaru et al have reported the relationship between FABP7 and Wnt/β-catenin pathway [ 55 ].…”

Section: Discussionmentioning

confidence: 87%

Metastatic Tumor Cell-Specific FABP7 Promotes NSCLC Metastasis via Inhibiting β-Catenin Degradation

Bai

Yang

et al. 2022

Cells

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Metastasis accounts for 90% of cancer-related deaths and represents a prominent malignant feature in non-small cell lung cancer (NSCLC), while tumor cell-specific mechanisms and molecules pivotal for the metastatic capacity remain unclear. By analyzing single-cell RNA sequencing data, we found that fatty acid binding protein 7 (FABP7) was specifically up-regulated in tumor cells of metastatic NSCLC patients and might be a prognostic indicator for poor survival. Experimental studies based on NSCLC cell lines showed that FABP7 promoted the metastatic competencies of NSCLC cells in vitro and in vivo. Mechanistically, we demonstrated that FABP7 was important to canonical Wnt signaling activation and competitively inhibited the interaction between β-catenin and components of its cytoplasmic degradation complex, thereby repressing the phosphorylation-dependent ubiquitination and degradation of β-catenin. Our present study identifies FABP7 as a metastatic tumor cell-specific pro-metastatic gene and uncovers a previously unknown regulatory mechanism underlying Wnt hyperactivation via FABP7-impaired cytoplasmic β-catenin degradation, implicating a novel molecule in regulating NSCLC metastasis.

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Section: Discussionmentioning

confidence: 87%

Metastatic Tumor Cell-Specific FABP7 Promotes NSCLC Metastasis via Inhibiting β-Catenin Degradation

Bai

Yang

et al. 2022

Cells

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“…It has been reported that docosahexaenoic acid (DHA), which is preferentially bound by FABP7, induced nuclear translocation of FABP7, followed by higher rate of migration [ 16 ]. In addition, although wild‐type FABP7 is shown to facilitate melanoma proliferation and glioma metastasis [ 16 , 29 ], the mutation in lipid‐binding domain of FABP7, which makes nuclear localization impossible, does not change these effect, suggesting that the interaction between FABP7 and its ligands is critically essential for nuclear localization of FABP7 and activity in tumor biology. Interestingly, it has been reported that IDH1mut induced altered lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

et al. 2021

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Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild‐type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular‐targeted therapies is of paramount importance. Fatty acid‐binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild‐type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin‐1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin‐1 promoter through controlling the nuclear acetyl‐CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7 . Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin‐1 expression, increased levels of histone acetylation, and increased levels of acetyl‐CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin‐1, and this mechanism is critically important for IDH1wt tumor biology.

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“…This is consistent with our binding assays that show little difference in binding affinity at 37ºC for any of the three ligands. 6. Binding pose heterogeneity explains changes to protein dynamics and mutation-resistant binding.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we focus on brain fatty acid binding protein (FABP7), which is found in various tissues but is particularly important in the brain. High expression levels of FABP7 are associated with increased cell proliferation, which is critical for neuron migration during brain development and has been linked to more invasive tumors and poor prognosis in glioblastomas, melanomas, and kidney and bladder cancer (5,6). Beyond its role in cell proliferation, genome-wide association studies have linked FABP7 to a variety of diseases, including schizophrenia (7) and autism (8).…”

Section: Introductionmentioning

confidence: 99%

Brain fatty acid binding protein exhibits non-preferential and mutation-resistant binding towards fatty acids

Bodnariuc

Lenz

Renaud-Young

et al. 2021

Preprint

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Members of the fatty acid binding protein (FABP) family function as intracellular transporters of long chain fatty acids and other hydrophobic molecules to different cellular compartments. Brain fatty acid binding protein (FABP7) exhibits ligand-directed differences in cellular transport behavior. For example, when FABP7 binds to docosahexaenoic acid (DHA), the complex relocates to the nucleus and influences transcriptional activity, whereas FABP7 bound with monosaturated fatty acids remain in the cytosol. We used a variety of biophysical techniques to enhance understanding of ligand-directed transport. Specifically, we examine how FABP7 binds to fatty acids, including saturated stearic acid (SA), monounsaturated oleic acid (OA), and polyunsaturated DHA. We find that at 37°C FABP7 has near equivalent binding affinities for the fatty acids, while at lower temperatures, FABP7 exhibits a preference for the unsaturated fatty acids. Therefore, nuclear localization of the FABP7-DHA complex cannot be explained by binding preferences. Using NMR spectroscopy and molecular dynamics simulations, we observe that DHA uniquely affects the portal region of FABP7, which could enhance the complex's nuclear localization. Mutations to purported critical binding residues (R126L and Y128F) have little effect on fatty acid binding, with molecular dynamics simulations revealing that the bound fatty acid can adopt binding poses that can accommodate the mutations.

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Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/β-Catenin Signaling

Cited by 17 publications

References 41 publications

Metastatic Tumor Cell-Specific FABP7 Promotes NSCLC Metastasis via Inhibiting β-Catenin Degradation

Metastatic Tumor Cell-Specific FABP7 Promotes NSCLC Metastasis via Inhibiting β-Catenin Degradation

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

Brain fatty acid binding protein exhibits non-preferential and mutation-resistant binding towards fatty acids

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