Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway
Open Access
- 28 July 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (37), 5626-5638
- https://doi.org/10.1038/s41388-021-01954-8
Abstract
We identified fermitin family member 2 (FERMT2, also known as kindlin-2) as a potential target in A375 cell line by siRNA library screening. Drugs that target mutant BRAF kinase lack durable efficacy in the treatment of melanoma because of acquired resistance, thus the identification of novel therapeutic targets is needed. Immunohistochemistry was used to identify kindlin-2 expression in melanoma samples. The interaction between kindlin-2 and Rac1 or p-Rac/Cdc42 guanine nucleotide exchange factor 6 (α-Pix) was investigated. Finally, the tumor suppressive role of kindlin-2 was validated in vitro and in vivo. Analysis of clinical samples and Oncomine data showed that higher levels of kindlin-2 predicted a more advanced T stage and M stage and facilitated metastasis and recurrence. Kindlin-2 knockdown significantly inhibited melanoma growth and migration, whereas kindlin-2 overexpression had the inverse effects. Further study showed that kindlin-2 could specifically bind to p-α-Pix(S13) and Rac1 to induce a switch from the inactive Rac1-GDP conformation to the active Rac1-GTP conformation and then stimulate the downstream MAPK pathway. Moreover, we revealed that a Rac1 inhibitor suppressed melanoma growth and metastasis and the combination of the Rac1 inhibitor and vemurafenib resulted in a better therapeutic outcome than monotherapy in melanoma with high kindlin-2 expression and BRAF mutation. Our results demonstrated that kindlin-2 promoted melanoma progression, which was attributed to specific binding to p-α-Pix(S13) and Rac1 to stimulate the downstream MAPK pathway. Thus, kindlin-2 could be a potential therapeutic target for treating melanoma.This publication has 56 references indexed in Scilit:
- Role of Activated Rac1/Cdc42 in Mediating Endothelial Cell Proliferation and Tumor Angiogenesis in Breast CancerPLOS ONE, 2013
- Identification of unique sensitizing targets for anti‐inflammatory CDDO‐Me in metastatic melanoma by a large‐scale synthetic lethal RNAi screeningPigment Cell & Melanoma Research, 2012
- Survival in BRAF V600–Mutant Advanced Melanoma Treated with VemurafenibThe New England Journal of Medicine, 2012
- Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein KinasesMicrobiology and Molecular Biology Reviews, 2011
- Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulationNature, 2010
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaThe New England Journal of Medicine, 2010
- The MAPK pathway in melanomaCurrent Opinion in Oncology, 2008
- Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancerOncogene, 2007
- Clinical and Microbiologic Study of Periodontitis Associated With Kindler SyndromeThe Journal of Periodontology, 2003
- Mutations of the BRAF gene in human cancerNature, 2002