Fbxo45‐mediated NP‐STEP₄₆ degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer

Abstract

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‐STEP46, 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.

Fbxo45 facilitates the malignant progression of breast cancer by targeting Bim for ubiquitination and degradation

“…Wu et al reported that FBXO45 regulated the ubiquitination and degradation of USP49 and accelerated the tumor progression in pancreatic cancer [ 36 ]. FBXO45 maintained ERK activity via targeting NP-STEP46 degradation in lung cancer [ 37 ]. Cao et al reported that lncRNA CACNA1C-AS2 regulated the expression of FBXO45 and PI3K/Akt/mTOR pathways, contributing to suppression of invasion, migration and proliferation in glioma [ 38 ].…”