Back to Search
Start Over
DLGAP1-AS2–Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma
- Source :
- Cancer Research. 82:2887-2903
- Publication Year :
- 2022
- Publisher :
- American Association for Cancer Research (AACR), 2022.
-
Abstract
- Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most patients with SCC experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and to explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein–coupled receptors formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2–targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents. Significance: This study identifies D-AS2 as a targetable lipid-related long noncoding RNA that increases phospholipase D activity to promote YAP signaling, triggering chemoresistance in SCC.
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 82
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....7e1e05f7eef878f6d7d2dbcea5a0153c