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

Yoshiteru Kagawa, Banlanjo Abdulaziz Umaru, Masayuki Kanamori, Ryo Zama, Subrata Kumar Shil, Hirofumi Miyazaki, Shuhei Kobayashi, Tunyanat Wannakul, Shuhan Yang, Teiji Tominaga, Yuji Owada

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalMolecular Oncology
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • acetyl-CoA
  • caveolae
  • caveolin-1
  • fatty acid-binding protein 7
  • isocitrate dehydrogenase 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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