SOX2 as a novel contributor of oxidative metabolism in melanoma cells

Abstract

BackgroundDeregulated metabolism is a hallmark of cancer and recent evidence underlines that targeting tumor energetics may improve therapy response and patient outcome. Despite the general attitude of cancer cells to exploit the glycolytic pathway even in the presence of oxygen (aerobic glycolysis or “Warburg effect”), tumor metabolism is extremely plastic, and such ability to switch from glycolysis to oxidative phosphorylation (OxPhos) allows cancer cells to survive under hostile microenvironments. Recently, OxPhos has been related with malignant progression, chemo-resistance and metastasis. OxPhos is induced under extracellular acidosis, a well-known characteristic of most solid tumors, included melanoma.MethodsTo evaluate whether SOX2 modulation is correlated with metabolic changes under standard or acidic conditions, SOX2 was silenced and overexpressed in several melanoma cell lines. To demonstrate that SOX2 directly represses HIF1A expression we used chromatin immunoprecipitation (ChIP) and luciferase assay.ResultsIn A375-M6 melanoma cells, extracellular acidosis increases SOX2 expression, that sustains the oxidative cancer metabolism exploited under acidic conditions. By studying non-acidic SSM2c and 501-Mel melanoma cells (high- and very low-SOX2 expressing cells, respectively), we confirmed the metabolic role of SOX2, attributing SOX2-driven OxPhos reprogramming to HIF1α pathway disruption.ConclusionsSOX2 contributes to the acquisition of an aggressive oxidative tumor phenotype, endowed with enhanced drug resistance and metastatic ability.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0297-z) contains supplementary material, which is available to authorized users.

Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

“…Transient treatment of A375-M6 melanoma cells with acidic medium increases expression of SOX2 with respect to control cancer cells grown in standard medium (125). Extracellular acidosis induces a metabolic switch toward OXPHOS and a concurrent slowdown of acidic cancer cells to a more glycolytic metabolism (126).…”

“…Extracellular acidosis induces a metabolic switch toward OXPHOS and a concurrent slowdown of acidic cancer cells to a more glycolytic metabolism (126). The silencing of SOX2 gene shifts the metabolism of acidic melanoma cells toward glycolysis, thus making cancer cells less vulnerable to metformin treatment (125,126). SOX2 is a transcription factor regulating, under acidic condition, the metabolic shift toward OXPHOS and downregulates HIF-1α by binding to its promoter (125,126).…”

“…The silencing of SOX2 gene shifts the metabolism of acidic melanoma cells toward glycolysis, thus making cancer cells less vulnerable to metformin treatment (125,126). SOX2 is a transcription factor regulating, under acidic condition, the metabolic shift toward OXPHOS and downregulates HIF-1α by binding to its promoter (125,126). Recent studies highlighted that the extracellular acidity of melanoma TME may provide an environment sustaining dormancy of melanoma cells, which exhibit low replication rate, high resistance to apoptosis and autophagy (127).…”

uPAR Knockout Results in a Deep Glycolytic and OXPHOS Reprogramming in Melanoma and Colon Carcinoma Cell Lines

“…Human melanoma A375p (CRL-1619) and colon cancer HCT 116 (CCL-247) cell lines were obtained from American Type Culture Collection while the human melanoma cell line A375-M6 was isolated from lung metastasis of SCID bg/bg mice IV injected with A375p [21] and grown in DMEM with 10% fetal bovine serum (Euroclone, Milano, Italy). Cells were tested every two weeks for Mycoplasma by PCR using two universal primers (MGSO and GPO1) [22].…”

The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells

“…Melanoma cell lines A375M6 [20] and M21 (kindly provided by Dr. Antony Montgomery, The Scripps Research Institute, La Jolla, CA), prostate cell line PC3 (purchased from the American Type Culture Collection, ATCC, Rockville, MD) and colon cancer cell line HCT116 (a kind gift of Dr. Matteo Lulli, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Italy) [30], STR profiled and mycoplasma tested, were cultured in DMEM 4.5 g/l glucose, 2 mM L-glutamine, and 10% FBS (Euroclone, Milan Italy). The chronic extracellular acidic condition was mimicked in vitro as previously reported [11].…”