Open AccessFbxo45‐mediated NP‐STEP 46 degradation via K6 ‐linked ubiquitination sustains ERK activity in lung cancer
Author(s) -
Wang Qian,
Xu Ci,
Cai Renjie,
An Weishu,
Yuan Haihua,
Xu Ming
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13290
Subject(s) - mapk/erk pathway , ubiquitin , chemistry , microbiology and biotechnology , lung cancer , degradation (telecommunications) , cancer research , biology , biochemistry , phosphorylation , medicine , computer science , gene , telecommunications
Lung cancer is one of the most threatening malignant tumors to human health. Epidermal growth factor receptor ( EGFR )‐targeted therapy is a common and essential means for the clinical treatment of lung cancer. However, drug resistance has always affected the therapeutic effect and survival rate in non‐small cell lung cancer ( NSCLC ). Tumor heterogeneity is a significant reason, yielding various drug resistance mechanisms, such as EGFR ‐dependent or ‐independent extracellular signal‐regulated kinase 1 and/or 2 ( ERK1 /2) activation in NSCLC . To examine whether this aberrant activation of ERK1 /2 is related to the loss of function of its specific phosphatase, a series of in vitro and in vivo assays were performed. We found that F‐box/ SPRY domain‐containing protein 1 ( Fbxo45 ) induces ubiquitination of NP‐STEP 46 , an active form of striatal‐enriched protein tyrosine phosphatase, with a K6 ‐linked poly‐ubiquitin chain. This ubiquitination led to proteasome degradation in the nucleus, which then sustains the aberrant level of phosphorylated‐ERK ( pERK ) and promotes tumor growth of NSCLC . Fbxo45 silencing can significantly inhibit cell proliferation and tumor growth. Moreover, NSCLC cells with silenced Fbxo45 showed great sensitivity to the EGFR tyrosine kinase inhibitor ( TKI ) afatinib. Here, we first report this critical pERK maintenance mechanism, which might be independent of the upstream kinase activity in NSCLC . We propose that inhibiting Fbxo45 may combat the issue of drug resistance in NSCLC patients, especially combining with EGFR‐TKI therapy.