GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-beta-dependent apoptotic signalling.
Defining apoptosis-regulatory cascades of the epithelium is important for understanding carcinogenesis, since cancer cells are considered to arise as a result of the collapse of the cascades. We previously reported that a novel gene GASDERMIN (GSDM) is expressed in the stomach but suppressed in gastric cancer cell lines. Furthermore, in this study, we demonstrated that GSDM is expressed in the mucus-secreting pit cells of the gastric epithelium and frequently silenced in primary gastric cancers. We found that GSDM has a highly apoptotic activity and its expression is regulated by a transcription factor LIM domain only 1 (LMO1) through a sequence to which Runt-related transcription factor 3 (RUNX3) binds, in a GSDM promoter region. We observed coexpression of GSDM with LMO1, RUNX3 and type II transforming growth factor-beta receptor (TGF-betaRII) in the pit cells, and found that TGF-beta upregulates the LMO1- and GSDM-expression in the gastric epithelial cell line and induces apoptosis, which was confirmed by the finding that the apoptosis induction is inhibited by suppression of each LMO1-, RUNX3- and GSDM expression, respectively. The present data suggest that TGF-beta, LMO1, possibly RUNX3, and GSDM form a regulatory pathway for directing the pit cells to apoptosis.
Saeki
N
N
Center for Medical Genomics, Genetics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Kim
D H
DH
Usui
T
T
Aoyagi
K
K
Tatsuta
T
T
Aoki
K
K
Yanagihara
K
K
Tamura
M
M
Mizushima
H
H
Sakamoto
H
H
Ogawa
K
K
Ohki
M
M
Shiroishi
T
T
Yoshida
T
T
Sasaki
H
H
D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060588:LIM Domain Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D024363:Transcription Initiation Site; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000094524:Gasdermins
D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C485887:GSDMA protein, human; D000094524:Gasdermins; C065072:LMO1 protein, human; C493729:Runx3 protein, human