miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

Young-Jun Jeon, Taewan Kim, Dongju Park, Gerard J. Nuovo, Siyeon Rhee, Pooja Joshi, Bum-Kyu Lee, Johan Jeong, Sung-suk Suh, Jeff E. Grotzke, Sung-Hak Kim, Jieun Song, Hosung Sim, Yonghwan Kim, Yong Peng, Youngtae Jeong, Michela Garofalo, Nicola Zanesi, Jonghwan Kim, Guang Liang, Ichiro Nakano, Peter Cresswell, Patrick Nana-Sinkam, Ri Cui () and Carlo M. Croce ()
Additional contact information
Young-Jun Jeon: The Ohio State University
Taewan Kim: The Ohio State University
Dongju Park: The Ohio State University
Gerard J. Nuovo: The Ohio State University
Siyeon Rhee: Stanford University
Pooja Joshi: The Ohio State University
Bum-Kyu Lee: The University of Texas at Austin
Johan Jeong: Stanford University
Sung-suk Suh: Mokpo National University
Jeff E. Grotzke: Yale University School of Medicine
Sung-Hak Kim: Chonnam National University
Jieun Song: The Ohio State University
Hosung Sim: The Ohio State University
Yonghwan Kim: Sookmyung Woman’s University
Yong Peng: The Ohio State University
Youngtae Jeong: Stanford University School of Medicine
Michela Garofalo: The Ohio State University
Nicola Zanesi: The Ohio State University
Jonghwan Kim: The University of Texas at Austin
Guang Liang: Wenzhou Medical University, Wenzhou
Ichiro Nakano: University of Alabama at Birmingham
Peter Cresswell: Yale University School of Medicine
Patrick Nana-Sinkam: The Ohio State University
Ri Cui: The Ohio State University
Carlo M. Croce: The Ohio State University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07561-8

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