ZNF322A-mediated protein phosphorylation induces autophagosome formation through modulation of IRS1-AKT glucose uptake and HSP-elicited UPR in lung cancer

Journal of Biomedical Science - Tập 27 Số 1 - 2020
Chantal Hoi Yin Cheung1, Chia‐Lang Hsu1, Tung‐Ching Lin1, Wei Ting Chen1, Yi‐Ching Wang2, Hsuan Cheng Huang3, Hsueh‐Fen Juan1
1Department of Life Science, National Taiwan University, Taipei 10617, Taiwan
2Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101 Taiwan
3Institute of Biomedical Informatics, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 11221, Taiwan

Tóm tắt

Abstract 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.

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Journal of Biomedical Science

Tập 27 Số 1

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