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.

• Authors: Qian Wang, Ci Xu, Renjie Cai, Weishu An, Haihua Yuan, Ming Xu
• Journal: Molecular oncology (Mol Oncol) Vol. 16 Issue 16 Pg. 3017-3033 (08 2022) ISSN: 1878-0261 [Electronic] United States
• PMID: 35838331 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• F-Box Proteins
• FBXO45 protein, human
• Protein Kinase Inhibitors
• ErbB Receptors

Topics

• Carcinoma, Non-Small-Cell Lung (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors (metabolism)
• F-Box Proteins (genetics, metabolism)
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Ubiquitination