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; Carlo M. Croce

doi:10.1038/s41467-018-07561-8

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 LiangIchiro Nakano, Peter Cresswell, Patrick Nana-Sinkam, Ri Cui, Carlo M. Croce

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English
Article number	5110
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07561-8
State	Published - 1 Dec 2018
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-018-07561-8

Cite this

Jeon, Y. J., Kim, T., Park, D., Nuovo, G. J., Rhee, S., Joshi, P., Lee, B. K., Jeong, J., Suh, S. S., Grotzke, J. E., Kim, S. H., Song, J., Sim, H., Kim, Y., Peng, Y., Jeong, Y., Garofalo, M., Zanesi, N., Kim, J., ... Croce, C. M. (2018). miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC. Nature Communications, 9(1), Article 5110. https://doi.org/10.1038/s41467-018-07561-8

@article{51a599b85bf94154b1dd3fb2c187b4b1,

title = "miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC",

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.",

author = "Jeon, \{Young Jun\} and Taewan Kim and Dongju Park and Nuovo, \{Gerard J.\} and Siyeon Rhee and Pooja Joshi and Lee, \{Bum Kyu\} and Johan Jeong and Suh, \{Sung suk\} and Grotzke, \{Jeff E.\} and Kim, \{Sung Hak\} and Jieun Song and Hosung Sim and Yonghwan Kim and Yong Peng and Youngtae Jeong and Michela Garofalo and Nicola Zanesi and Jonghwan Kim and Guang Liang and Ichiro Nakano and Peter Cresswell and Patrick Nana-Sinkam and Ri Cui and Croce, \{Carlo M.\}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07561-8",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Jeon, YJ, Kim, T, Park, D, Nuovo, GJ, Rhee, S, Joshi, P, Lee, BK, Jeong, J, Suh, SS, Grotzke, JE, Kim, SH, Song, J, Sim, H, Kim, Y, Peng, Y, Jeong, Y, Garofalo, M, Zanesi, N, Kim, J, Liang, G, Nakano, I, Cresswell, P, Nana-Sinkam, P, Cui, R & Croce, CM 2018, 'miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC', Nature Communications, vol. 9, no. 1, 5110. https://doi.org/10.1038/s41467-018-07561-8

TY - JOUR

T1 - miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

AU - Jeon, Young Jun

AU - Kim, Taewan

AU - Park, Dongju

AU - Nuovo, Gerard J.

AU - Rhee, Siyeon

AU - Joshi, Pooja

AU - Lee, Bum Kyu

AU - Jeong, Johan

AU - Suh, Sung suk

AU - Grotzke, Jeff E.

AU - Kim, Sung Hak

AU - Song, Jieun

AU - Sim, Hosung

AU - Kim, Yonghwan

AU - Peng, Yong

AU - Jeong, Youngtae

AU - Garofalo, Michela

AU - Zanesi, Nicola

AU - Kim, Jonghwan

AU - Liang, Guang

AU - Nakano, Ichiro

AU - Cresswell, Peter

AU - Nana-Sinkam, Patrick

AU - Cui, Ri

AU - Croce, Carlo M.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85057603360

U2 - 10.1038/s41467-018-07561-8

DO - 10.1038/s41467-018-07561-8

M3 - Article

C2 - 30504895

AN - SCOPUS:85057603360

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5110

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this