The Elongin BC Complex Negatively Regulates AXL and Marks a Differentiated Phenotype in Melanoma

Autor: Sebastiaan M. Schieven, Joleen J.H. Traets, Alex v. Vliet, Martijn v. Baalen, Ji-Ying Song, Marcos Da Silva Guimaraes, Thomas Kuilman, Daniel S. Peeper
Rok vydání: 2023
Předmět:
Zdroj: Molecular Cancer Research. 21:428-443
ISSN: 1557-3125
1541-7786
DOI: 10.1158/1541-7786.mcr-22-0648
Popis: High expression of the receptor tyrosine kinase AXL is implicated in epithelial-to-mesenchymal transition, cancer progression, and therapy resistance. For example, AXL is abundant in BRAF mutant melanomas progressing on targeted BRAF/MEK inhibition. Therefore, AXL is thought to represent an attractive therapeutic target. This notwithstanding, little is known about the mechanisms governing expression of AXL. Here, we describe a FACS-based whole-genome-wide CRISPR-Cas9 screen to uncover regulators of AXL expression. We identified several genes, inactivation of which led to increased AXL expression. Most remarkable was the identification of five components that associate with the Elongin BC heterodimer. Elongin B/C engage in multiple protein–protein interactions, including the transcription factor complex subunit Elongin A, the von Hippel-Lindau (VHL) tumor suppressor protein, and members of the SOCS-box protein family. The screen identified ELOB, ELOC, SOCS5, UBE2F, and RNF7, each of which we demonstrate to serve as an inhibitor of AXL expression. Although the AXL promoter contains hypoxia response elements and Elongin B/C are found in the VHL complex, Elongin B/C unexpectedly regulate AXL independently of hypoxia. Instead, we demonstrate that the Elongin BC complex interacts with AXL through ELOB, and contributes to proteasomal AXL turnover. RNA-sequencing and IHC analyses of melanoma patient-derived xenografts and clinical samples revealed a negative association between Elongin B/C and dedifferentiation. Together, the Elongin BC complex regulates AXL and marks a differentiated melanoma phenotype. Implications: This study identifies the Elongin BC complex as a key regulator of AXL expression and marker of melanoma differentiation.
Databáze: OpenAIRE
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