1. Academic Validation
  2. DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma

DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma

  • Cancer Res. 2022 Aug 16;82(16):2887-2903. doi: 10.1158/0008-5472.CAN-22-0717.
Yabing Nan  # 1 Qingyu Luo  # 1 Xiaowei Wu  # 1 Shi Liu 1 Pengfei Zhao 1 Wan Chang 1 Aiping Zhou 2 Zhihua Liu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
  • 2 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
  • # Contributed equally.
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.

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