DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ

Abstract

Objectives Cancer stem cells (CSCs) have been identified to correlate with the initiation and metastasis of tumours, and DNA damage-inducible transcript 3 (DDIT3) is associated with the poor prognosis in gastric cancer (GC). However, whether DDIT3 mediates CSCs stemness in GC is still unclear. Methods Microarray analysis and Gene Ontology (GO) were conducted to identify the differentially expressed genes in GC tissues from GC patients. The interaction between DDIT3 and CEBPb was determined using immunoprecipitation (IP) analysis. Key findings Herein, microarray analysis showed that DDIT3 expression is increased in GC tissues. qRT-PCR confirmed that DDIT3 is significantly increased in GC tissues and cancer cell lines compared with healthy tissues and normal cell lines, individually. Genetic overexpression of DDIT3 enhanced GC cell proliferation, colony-forming ability, sphere formation and CSCs stemness. Mechanistically, DDIT3 directly up-regulated the expression of transcription factor CEBPb, leading to the increased expression of CSCs markers SOX2, NANOG, OCT4 and CD133 in gastric CSCs. Genetic downregulation of CEBPb significantly abolishes DDIT3-mediated increased cell proliferation, colony-forming ability, sphere formation and CSCs stemness. Conclusion Our results demonstrated that DDIT3 promotes CSCs stemness by up-regulating CEBPb in GC that provides novel targets for the further GC therapy.

Induction of Apoptosis and Modulation of Caspase Activity on MCF-7 Human Breast Cancer Cells by Bioactive Fractionated Cocoa Leaf Extract

“…The DDIT3 gene, also known as GADD153 or CHOP, encodes a transcription factor that belongs to the CCAAT/ enhancer binding protein (C/EBP) family (Xavier et al, 2018). Upon activation, DDIT3 plays a pivotal role in promoting the up-regulation of key signaling molecules that regulate the endoplasmic reticulum (ER) stress response and DNA damage response, inducing cell cycle arrest and apoptosis by halting progression from G1 to S phase (Lin et al, 2020). Interestingly, we found that the DDIT3 gene was up-regulated in MCF-7 cells, as compared to the normal control group (Table 1).…”

CEBPB-mediated upregulation of SERPINA1 promotes colorectal cancer progression by enhancing STAT3 signaling

“…Studies have shown that CEBPB plays an important role in tumors. In a study on gastric cancer, it was shown that DDIT3 can directly upregulate the transcription factor CEBPB, thereby increasing the stemness of gastric cancer cells and the expression of stem cell markers: SOX2, NANOG, OCT4, and CD133 [ 36 ]. At the same time, there are also studies reporting that CEBPB plays a pro-cancer role in bladder cancer [ 37 ].…”

Integrated Bioinformatics Analysis Identified ASNS and DDIT3 as the Therapeutic Target in Castrate-Resistant Prostate Cancer

“…In addition, our findings indicate a role for DDIT3 in cancer stem cells. Overexpression of DDIT3 promotes stemness of cancer stem cells in gastric cancer by regulating CEBPβ [ 37 ]. Zhang et al showed that DDIT3 also participates in PCa progression, including invasion capacity and cell proliferation.…”