Aerobic glycolysis tunes YAP / TAZ transcriptional activity

Abstract

Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro-tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth-promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/ TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro-tumorigenic activities such as YAP/TAZ.

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

“…The dynamics of this compensatory relationship, however, await further mechanistic definition in vivo. Moreover, cellular energy status has been implicated as a potent regulator of YAP/TAZ activity either through AMP-kinase activation (9, 10), induction of aerobic glycolysis (40), or mevalonate metabolism (41). A connection between YAP activity and glutamine synthetase (GS) has been reported in the liver, where GS expression can predominate (42,43).…”

Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways

“…When cells experience a condition of energy stress (i.e., low levels of ATP availability), AMPK phosphorylates TSC2 (tuberous sclerosis complex 2), promoting the inhibitory activity of TSC1-TSC2 towards the mTOR (mammalian target of rapamycin) complex. By this mechanism, AMPK promotes the activation of alternative catabolic pathways to reestablish ATP levels, thus maintaining energy homeostasis [29][30][31].Recently, a connection between glucose and YAP/TAZ activity has been observed [32][33][34][35]. Inhibition of glucose uptake and of glycolysis, or a shift from aerobic glycolysis to oxidative phosphorylation, induced a corresponding inhibition of YAP/TAZ activity in human cultured cells.…”

“…Inhibition of glucose uptake and of glycolysis, or a shift from aerobic glycolysis to oxidative phosphorylation, induced a corresponding inhibition of YAP/TAZ activity in human cultured cells. This mechanism appears to be conserved because inhibition of glycolysis in Drosophila inhibited established Yorkie target genes and counteracted Yorkie growth-promoting activity [32]. Mechanistically, glucose regulates the stability of the transcriptional complex with TEAD factors [32,34,35], which reflects the regulation of YAP/TAZ binding to its endogenous promoters and the widespread regulation of YAP/TAZ target genes in mammary cell lines upon inhibition of glucose uptake [32].…”

“…Going forward, it will be important to understand under which conditions, in addition to direct activation by small molecules, AMPK is instrumental for inhibiting YAP/TAZ activity. For example, the functional requirement of AMPK in the regulation of YAP/TAZ by glucose remains unclear: results for direct inhibition of YAP/TAZ by AMPK activators (i.e., in luciferase assays) were inconsistent and depended on the cell line, despite efficient AMPK modulation [32,33]. In addition, the rescue of YAP/TAZ activity by pharmacological blockade or knockdown of AMPK in cells deprived of glucose was either partial [34] or ineffective [32], respectively.…”

Compartmentation of Metabolites in Regulating Epigenomes of Cancer

“…nucleus is the dominant way for EERMs to be involved in epigenetic modifications. But more and more, metabolic enzymes are identified within the nucleus with important functions in regulating gene expression by serving as cofactors of transcriptional regulatory complexes (18,19,(20)(21)(22)(23)(24)(25)(26)(27)(28). Some of these factors actually have the enzymatic activities to produce EERMs locally along with other nuclear events such as gene transcription and DNA replication (18,19,(23)(24)(25)(26).…”