Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB)

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  • Komiyama Hiromitsu
    Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics Department of Coloproctological Surgery, Juntendo University, School of Medicine
  • Aoki Aya
    Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics Departments of Neurosurgery, Juntendo University, Shizuoka Hospital
  • Tanaka Shigekazu
    Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics
  • Maekawa Hiroshi
    Departments of Surgery, Juntendo University, Shizuoka Hospital
  • Kato Yoriko
    Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics
  • Wada Ryo
    Departments of Pathology, Juntendo University, Shizuoka Hospital
  • Maekawa Takeo
    Departments of Surgery, Juntendo University, Shizuoka Hospital
  • Tamura Masaru
    Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics
  • Shiroishi Toshihiko
    Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics

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GASDERMIN B (GSDMB) belongs to the novel gene family GASDERMIN (GSDM). All GSDM family members are located in amplicons, genomic regions often amplified during cancer development. Given that GSDMB is highly expressed in cancerous cells and the locus resides in an amplicon, GSDMB may be involved in cancer development and/or progression. However, only limited information is available on GSDMB expression in tissues, normal and cancerous, from cancer patients. Furthermore, the molecular mechanisms that regulate GSDMB expression in gastric tissues are poorly understood. We investigated the spatiotemporal expression patterns of GSDMB in gastric cancer patients and the 5’ regulatory sequences upstream of GSDMB. GSDMB was not expressed in the majority of normal gastric-tissue samples, and the expression level was very low in the few normal samples with GSDMB expression. Most pre-cancer samples showed moderate GSDMB expression, and most cancerous samples showed augmented GSDMB expression. Analysis of genome sequences revealed that an Alu element resides in the 5’ region upstream of GSDMB. Reporter assays using intact, deleted, and mutated Alu elements clearly showed that this Alu element positively regulates GSDMB expression and that a putative IKZF binding motif in this element is crucial to upregulate GSDMB expression.<br>

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