miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.
Young-Jun JeonTaewan KimDongju ParkGerard J NuovoSiyeon RheePooja JoshiBum-Kyu LeeJohan JeongSung-Suk SuhJeff E GrotzkeSung-Hak KimJieun SongHosung SimYong-Hwan KimYong PengYoungtae JeongMichela GarofaloNicola ZanesiJonghwan KimGuang LiangIchiro NakanoPeter CresswellPatrick Nana-SinkamRi CuiCarlo M CrocePublished in: Nature communications (2018)
Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.
Keyphrases
- small cell lung cancer
- papillary thyroid
- squamous cell carcinoma
- endoplasmic reticulum stress
- squamous cell
- advanced non small cell lung cancer
- transcription factor
- lymph node metastasis
- cell therapy
- stem cells
- long non coding rna
- gene expression
- bone marrow
- replacement therapy
- single cell
- young adults
- climate change
- copy number
- small molecule
- binding protein
- mass spectrometry
- protein protein