LNK suppresses interferon signaling in melanoma

Ling-Wen Ding, Qiao-Yang Sun (), Jarem J. Edwards, Lucia Torres Fernández, Xue-Bin Ran, Si-Qin Zhou, Richard A. Scolyer, James S. Wilmott, John F. Thompson, Ngan Doan, Jonathan W. Said, Nachiyappan Venkatachalam, Jin-Fen Xiao, Xin-Yi Loh, Maren Pein, Liang Xu, David W. Mullins, Henry Yang, Lin De-Chen and H. Phillip Koeffler
Additional contact information
Ling-Wen Ding: Cancer Science Institute of Singapore, National University of Singapore
Qiao-Yang Sun: Cancer Science Institute of Singapore, National University of Singapore
Jarem J. Edwards: Melanoma Institute Australia, The University of Sydney
Lucia Torres Fernández: Cancer Science Institute of Singapore, National University of Singapore
Xue-Bin Ran: Cancer Science Institute of Singapore, National University of Singapore
Si-Qin Zhou: Cancer Science Institute of Singapore, National University of Singapore
Richard A. Scolyer: Melanoma Institute Australia, The University of Sydney
James S. Wilmott: Melanoma Institute Australia, The University of Sydney
John F. Thompson: Melanoma Institute Australia, The University of Sydney
Ngan Doan: Santa Monica-University of California, Los Angeles Medical Center
Jonathan W. Said: Santa Monica-University of California, Los Angeles Medical Center
Nachiyappan Venkatachalam: Cancer Science Institute of Singapore, National University of Singapore
Jin-Fen Xiao: Cancer Science Institute of Singapore, National University of Singapore
Xin-Yi Loh: Cancer Science Institute of Singapore, National University of Singapore
Maren Pein: Cancer Science Institute of Singapore, National University of Singapore
Liang Xu: Cancer Science Institute of Singapore, National University of Singapore
David W. Mullins: Geisel School of Medicine at Dartmouth
Henry Yang: Cancer Science Institute of Singapore, National University of Singapore
Lin De-Chen: Cedars-Sinai Medical Center, UCLA School of Medicine
H. Phillip Koeffler: Cancer Science Institute of Singapore, National University of Singapore

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.

Date: 2019
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DOI: 10.1038/s41467-019-09711-y

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