Examinando por Autor "Chauhan, J"

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Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity.
(Mol Cell, 2020-01-02) Vivas-García, Yurena; Falletta, P; Liebing, J; Louphrasitthiphol, P; Feng, Y; Chauhan, J; Scott, DA; Glodde, N; Chocarro-Calvo, A; Bonham, S; Osterman, A; Fischer, R; Ronai, Z; García-Jiménez, C; Hölzel, M; Goding, CR
Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.
Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer.
(2020-06-30) Gutiérrez-Salmerón, M; García-Martínez, JM; Martinez-Useros, J; Fernández-Aceñedo, MJ; Viollet, B; Olivier, S; Chauhan, J; Lucena, SR; De la Vieja, A; De la Vieja, CR; Chocarro-Calvo, A; García-Jiménez, C
Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type-specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply-demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards β-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/β-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.