Baille, D. | Search bioRxiv

bioRxiv2025

Selective mRNA translation determines adaptative mutability of melanoma cells to anti-BRAF/MEK combination therapy

During their inevitable evolution towards acquired resistance to anti-cancer targeted therapies, cancer cells adopt distinct gene expression profiles that allow them to transiently adapt to and tolerate the treatment. Similar to bacterial cells that transiently tolerate antibiotics, cancer cells surviving therapy can increase their mutation rate, enhancing the likelihood of acquiring resistance-conferring mutations and evolving into resistant cells. This adaptive mutability has been linked to transcriptional reprogramming of DNA damage repair mechanisms and effective therapeutic strategies to target such mechanisms are currently lacking. Here we show that translational control mediates the adaptive mutability of melanoma drug-tolerant cells by regulating the translation of the error-prone non-homologous end joining (NHEJ) component 53BP1. The specific inhibition of 5UTR-driven 53BP1 mRNA translation was sufficient to impair NHEJ and mutability. We found that the eIF4A RNA helicase, a key component of the eIF4F translation complex, regulates 53BP1 mRNA translation. Consequently, targeting the eIF4A with two small molecule inhibitors significantly delays the acquisition of resistance to combination of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutant melanoma xenograft models and cell lines by reducing the mutability of drug-tolerant cells. Our results demonstrate that a standard-of-care therapy for melanoma, by engaging non-genetic adaptation driven at the translational level, contributes to the evolution of drug-tolerant melanoma cells toward acquired resistance.

cancer biology↗

bioRxiv2024

An extra-glycolytic function for hexokinase 2 as an RNA-binding protein regulating SOX10 mRNA translation in melanoma

Several studies have reported the importance of aerobic glycolysis in melanoma development. Although metabolic benefits of glycolysis have been extensively described in tumor cells, the extra-metabolic functions linked to this energetic pathway in melanoma growth and proliferation have not been clearly established yet. Recently, some key glycolytic enzymes, such as GAPDH and PKM2, were reported to regulate mRNA translation. Translational control of gene expression is considered as a critical effector in cancer biology, representing a highly promising area of research. Here, we report that Hexokinase 2 (HK2), a glucose kinase that catalyzes the first step of glycolysis, is an RNA binding protein (RBP) that regulates mRNA translation in melanoma. We show that siRNA-mediated HK2 depletion changes the translational landscape of melanoma cells. Polysome profiling experiments and RNA-Seq indicate that the translational regulation exerted by HK2 is partly independent of the metabolic status or the glycolytic pathway. We found that HK2 specifically regulates the translation of the mRNA encoding SOX10, a transcription factor implicated in the regulation of tumor initiation, maintenance and progression in melanoma. RNA-protein interaction assays, including crosslinking immunoprecipitation (CLIP), indicate that HK2 is an RBP whose interaction with RNA is independent of its hexokinase activity or subcellular localization. We also show that HK2 specifically associates with the 5 untranslated region (5UTR) of the SOX10 mRNA, and that several deletions in this region decreases both HK2-SOX10 mRNA association and SOX10 5 UTR-mediated translation. We further show that HK2-dependent SOX10 translational regulation is involved in melanoma cell proliferation and colony formation. Collectively, our data highlight a non-metabolic function of HK2, indicating that melanoma cells may enhance glycolysis for purposes beyond simple anabolism.

cancer biology↗