TRIB2 supports a high glycolytic phenotype in melanoma cells

Abstract

Metabolic adaptation plays a crucial role in driving the progression of human melanoma contributing to therapy resistance and disease relapse. The pseudo serine/threonine kinase Tribbles homolog 2 (TRIB2) is prominently expressed in melanoma tissue, promoting resistance to anti-cancer treatments and correlating with unfavorable clinical outcomes. Despite this understanding, the impact of TRIB2 expression on melanomas metabolic profile remains unexplored. Here we use UACC-62 melanoma cells which exhibit substantial endogenous expression of TRIB2 as well as engineered isogenic TRIB2 knock out (KO) cells to assess the effect of the loss of TRIB2 on metabolism. Our findings reveal that TRIB2-KO cells display reduced glycolytic activity and heightened vulnerability to pharmacological inhibition of oxidative metabolism, contrasting with the parental cell line. These metabolic and phenotypic changes are driven by TRIB2s coordinated regulation of multiple glycolytic genes, whose combined effect might produce the glycolytic phenotype observed in parental cells. Collectively, our results underscore important role of TRIB2 as a modulator of the metabolic shift implicated in therapy resistance. These insights highlight TRIB2 as a potential target for therapeutic intervention, aiming to counteract the metabolic adaptations driving melanomas resistance mechanisms. HighlightsO_LIMain problem in melanoma is the limited therapy efficacy due to resistance; C_LIO_LITRIB2 is a novel unexplored and druggable target; C_LIO_LITRIB2 expression contributes to increased glycolysis in melanoma cells; C_LIO_LITRIB2 is a driver of a metabolic switch that fuels therapy resistance. C_LI