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

Abstract

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.

The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis

“…In fact, it is well known that—besides cis -acting variants—differences in the levels of AS isoforms may be due to alterations in trans -acting factor levels [38]. Interestingly, variations in the expression of trans -acting factors, such as SR proteins and hnRNPs, were found also in cancer [39,40], in which a differential expression of GSDMB splicing isoforms was repeatedly evidenced [26,28,30]. Moreover, besides alterations in genotype-dependent AS, we also measured a significant downregulation in MS patients of the overall amount of GSDMB mRNA by digital RT-PCR on constitutively expressed exons (9–11) (see Supplementary Figure S4).…”

“…A differential expression of splicing isoforms was detected in gastrointestinal and hepatic cancers in respect to non-tumor tissues, with a correlation between an increased amount of shorter isoforms and cancer development and progression [26,30]. Moreover, in a study aimed at identifying polymorphisms associated with autoimmune/inflammatory diseases and affecting splicing, Morrison and colleagues [31] identified the rs11078928 (A > G) polymorphism, impacting on the invariant AG dinucleotide at the acceptor splice site of GSDMB intron 5.…”

Analysis of rs8067378 Polymorphism in the Risk of Uterine Cervical Cancer from a Polish Population and its Impact on Gasdermin B Expression

“…GSDMB expression is driven by two promoters: the cellular promoter and the Long Terminal Repeats-derived promoter [20–22]. The studied NC_000017.10:g.38051348A>G (rs8067378) SNP is situated 9.5 kb downstream of the GSDMB , in a region suggested to be a functional polymorphism as part of the transcriptional regulatory element and/or modulator of chromatin structure in this domain [23, 24].…”

Loss of conserved Gsdma3 self-regulation causes autophagy and cell death

“…In mouse, there are three homologues in the A cluster [Gasdermin A1-3 (Gsdma1, 2, 3)], four homologues in the C cluster (Gsdmc1, 2, 3,4), one homologue in the D cluster (Gsdmd) and no counterpart of human GSDMB [8]. GSDMA, GSDMC and GSDMD are all reported to be cancer suppressors, but GSDMB is considered to be an oncogene [9][10][11][12].…”