Abstract:Recent evidences suggest that stearoyl-CoA-desaturase 1 (SCD1), the enzyme involved in monounsaturated fatty acids synthesis, has a role in several cancers. We previously demonstrated that SCD1 is important in lung cancer stem cells survival and propagation. In this article, we first show, using primary cell cultures from human lung adenocarcinoma, that the effectors of the Hippo pathway, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are required for the generation… Show more
“…A recent study reveals that SCD 1 promotes nuclear localization and transcriptional activity of YAP/TAZ to regulate lung cancer stemness (Fig. 3a) [57]. The regulation of YAP/TAZ by SCD1 is at least in part dependent on Wnt/β-catenin pathway activity, but not dependent on the Hippo signaling pathway.…”
Section: Main Textmentioning
confidence: 96%
“…This in turn promotes β-catenin and YAP/TAZ accumulation in the nucleus to promote their target genes transcription (Fig. 3a) [57]. Fig.…”
In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.
“…A recent study reveals that SCD 1 promotes nuclear localization and transcriptional activity of YAP/TAZ to regulate lung cancer stemness (Fig. 3a) [57]. The regulation of YAP/TAZ by SCD1 is at least in part dependent on Wnt/β-catenin pathway activity, but not dependent on the Hippo signaling pathway.…”
Section: Main Textmentioning
confidence: 96%
“…This in turn promotes β-catenin and YAP/TAZ accumulation in the nucleus to promote their target genes transcription (Fig. 3a) [57]. Fig.…”
In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.
“…The stearoyl-CoA-desaturase 1 (SCD1) enzyme promotes fatty acid synthesis and it is demonstrated to regulate YAP and TAZ function promoting their activation and nuclear localization that is also dependent by β-catenin activation. This promotes stemness, increased cell proliferation and it is associated with a poor prognosis in lung cancer casuistries [238]. Moreover, the phosphofructokinase (PFK1) enzyme that is involved in glycolytic metabolic pathway induces YAP and TAZ activity [239]; conversely, under glucose starvation conditions, Hippo and AMPK are activated leading to YAP phosphorylation and inhibition [240].…”
p53 protein is a well-known tumor suppressor factor that regulates cellular homeostasis. As it has several and key functions exerted, p53 is known as “the guardian of the genome” and either loss of function or gain of function mutations in the TP53 coding protein sequence are involved in cancer onset and progression. The Hippo pathway is a key regulator of developmental and regenerative physiological processes but if deregulated can induce cell transformation and cancer progression. The p53 and Hippo pathways exert a plethora of fine-tuned functions that can apparently be in contrast with each other. In this review, we propose that the p53 status can affect the Hippo pathway function by switching its outputs from tumor suppressor to oncogenic activities. In detail, we discuss: (a) the oncogenic role of the protein complex mutant p53/YAP; (b) TAZ oncogenic activation mediated by mutant p53; (c) the therapeutic potential of targeting mutant p53 to impair YAP and TAZ oncogenic functions in human cancers.
“…YAP1 is a pleiotropic transcription factor that drives stemness through activation of the pluripotency cassette (OCT4, SOX2 and Nanog). Disruption of Hippo pathway leads to constitutive nuclear levels of YAP that in turn induces activation of lung cancer stem cells (Noto et al, 2017). Despite constitutive nuclear YAP1, H1299 con cells grown in 2D did not display upregulation of NANOG compared to H1299 RASSF1A and levels remain weak in both cell lines ( Fig EV3A).…”
Section: Yap Pathway Regulation Of P4ha2mentioning
Lung cancer remains the leading cause of cancer-related death due to poor treatment responses arising from tumor heterogeneity and epigenetic aberrations. Here we show that adverse prognosis associated with epigenetically silenced tumour suppressor RASSF1A is a consequence of increased extracellular matrix, tumour stiffness and metastatic dissemination in vivo and in vitro. We find that lung cancer cells with methylated RASSF1A display constitutive nuclear YAP1 and expression of prolyl4hydroxylase2 (P4HA2) into extracellular matrix that correlates with increases collagen deposition. Furthermore, we identify an epigenetic axis in tumour cells where elevated ECM impedes the intrinsic suppression of WNT signaling (via TPBG/5T4) triggering b-catenin-YAP1 activation and thus results in a cancer stem-like programming. As key drivers, we identified RASSF1A and P4HA2 mediating the ECM-dependent stemness and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverse these effects and increase levels of lung differentiation markers (TTF-1, Mucin5B) in vivo and in vitro. Our study identifies an epigenetic program to cancer stemness and metastatic progression of lung adenocarcinoma and P4HA2 as potential target for uncoupling ECM signals towards cancer stemness. D.P. designed the research, performed experiments and analysed data. Y.J. and A.R. assisted with animal work, I.V. provided and analysed LC-MS/MS, J.B. performed the fibrotic staining, C.B. performed AFM, E.O.N and D.P. wrote manuscript.
Conflict of interestThe authors declare no conflict of interest.
The paper explainedProblem Lung cancer is the leading cause of cancer-related death worldwide with limited improvement in survival over 30 years due to late diagnosis and poor therapeutic options. Epigenetic inactivation of RASSF1A correlates with lung cancer onset, metastasis, poor prognosis and therapeutic responses, however, mechanistic explanation for these clinical associations in human tumours has been lacking.
ResultsHere we demonstrate that RASSF1A methylation in lung adenocarcinomas is a consequence of triggering signals from ECM due to expression of P4HA2 into extracellular matrix, that in turn induces cancer stem-like cells programming and metastatic dissemination in vivo and in vitro. Re-expression of RASSF1A or inhibition of P4HA2 activity converses these processes and switch into lung cancer differentiation accompanied by better prognosis and clinical survival.
ImpactOur study demonstrates an importance of tumour microenvironment in epigenetic regulation of cancer stemness and metastatic progression of lung adenocarcinoma and targeting P4HA2 as a new anti-tumour therapy agent.
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