GSDME and its role in cancer: From behind the scenes to the front of the stage

Abstract

Gasdermin E (GSDME), a gene originally involved in hereditary hearing loss, has been associated with several types of cancer in the last two decades. Recently, GSDME was identified as a pore-forming molecule, which is activated following caspase-3-mediated cleavage resulting in so-called secondary necrosis following apoptotic cell death, or in primary necrotic cell death without an apoptotic phase, so-called pyroptosis-like. This implication in cell death execution suggests its potential role as a tumor suppressor. GSDME also exhibited a cancer type-specific differential methylation pattern between tumor tissues and normal cells, implying GSDME gene methylation as both a pan-cancer and cancer type-specific detection biomarker. A bit paradoxically, GSDME protein expression is considered to be less suited as biomarker, and although its ablation does not protect the cell against eventual cell death, its protein expression might still operate in tumor immunogenicity due to its capacity to induce (secondary) necrotic cell death, which has enhanced immunogenic properties. Additionally, GSDME gene expression has been shown to be associated with favorable prognosis following chemotherapy, and it could therefore be a potential predictive biomarker. We provide an overview of the different associations between GSDME gene methylation, gene expression and tumorigenesis, and explore their potential use in the clinic. Our review only focuses on GSDME and summarizes the current knowledge and most recent advances on GSDME's role in cancer formation, its potential as a biomarker in cancer and on its promising role in immunotherapies and antitumor immune response.

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ

“…The levels of c-myc protein were decreased to undetectable level after TPL treatment for 24 h. This powerful inhibitory effect is a comprehensive result from simultaneously repression protein stability and transcription of c-myc by TPL. GSDME is frequently silenced in human cancers due to hyper-methylation of promoter DNA [59], making cancer cells lack of GSDME are resistant to pyroptosis. It remains a challenge to kill cancers within dysfunction of cell death machinery.…”

Pyroptosis, metabolism, and tumor immune microenvironment

“…GSDME mutation was first identified to cause an autosomal dominant hearing impairment. 18 , 174 , 175 GSDME is mostly expressed in the cochlea, placenta, brain, female reproductive tract (especially the placenta), kidney, heart, and muscle. 36 In contrast to non‐tumoral tissues, expression of GSDME is limited in most cancers including gastric cancer, melanoma, CRC, invasive breast cancer, and other human cancers.…”

“…GSDME , also known as DFNA5 , is located on human chromosome 7p15.3, while Gsdme , also known as Dfna5 , is found on mouse chromosome 6B2.3. GSDME mutation was first identified to cause an autosomal dominant hearing impairment 18,174,175 . GSDME is mostly expressed in the cochlea, placenta, brain, female reproductive tract (especially the placenta), kidney, heart, and muscle 36 .…”

Pyroptotic and Necroptotic Cell Death in the Tumor Microenvironment and Their Potential to Stimulate Anti-Tumor Immune Responses

“…On the other hand, data on GSDME expression levels between cancer and normal samples are controversial: while the majority of translational studies have found downregulated levels of GDME in cancer compared to normal tissue, others have not found such differences. Even more puzzling, there was no clear correlation between GSDME methylation and GSDME expression levels in a number of studies ( 40 ). Overall, however, GSDME appears to represent a potent tumor suppressor gene ( 20 ).…”