- 作者: Chantal Hoi Yin Cheung, Chia-Lang Hsu, Tsai-Yu Lin, Wei-Ting Chen, Yi-Ching Wang, Hsuan-Cheng Huang and Hsueh-Fen Juan
- 作者服務機構: 1. Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan 2. Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, Taiwan 3. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan 4. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan 5. Institute of Biomedical Informatics, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 11221, Taiwan 6. Department of Life Science, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, 10617, Taiwan
- 中文摘要:
- 英文摘要:
Background
ZNF322A is an oncogenic transcription factor that belongs to the Cys2His2-type zinc-finger protein family. Accumulating evidence suggests that ZNF322A may contribute to the tumorigenesis of lung cancer, however, the ZNF322A-mediated downstream signaling pathways remain unknown.
Methods
To uncover ZNF322A-mediated functional network, we applied phosphopeptide enrichment and isobaric labeling strategies with mass spectrometry-based proteomics using A549 lung cancer cells, and analyzed the differentially expressed proteins of phosphoproteomic and proteomic profiles to determine ZNF322A-modulated pathways.
Results
ZNF322A highlighted a previously unidentified insulin signaling, heat stress, and signal attenuation at the post-translational level. Consistently, protein-phosphoprotein-kinase interaction network analysis revealed phosphorylation of IRS1 and HSP27 were altered upon ZNF322A-silenced lung cancer cells. Thus, we further investigated the molecular regulation of ZNF322A, and found the inhibitory transcriptional regulation of ZNF322A on PIM3, which was able to phosphorylate IRS1 at serine1101 in order to manipulate glucose uptake via the PI3K/AKT/mTOR signaling pathway. Moreover, ZNF322A also affects the unfolded protein response by phosphorylation of HSP27S82 and eIF2aS51, and triggers autophagosome formation in lung cancer cells.
Conclusions
These findings not only give new information about the molecular regulation of the cellular proteins through ZNF322A at the post-translational level, but also provides a resource for the study of lung cancer therapy. - 中文關鍵字:
- 英文關鍵字: Autophagy, Glucose starvation, Heat stress, Lung cancer, Phosphoproteomics, Proteomics, Zinc-finger protein