p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate ...in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.
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•p62 in preneoplastic lesions is important for HCC development regardless of etiology•Ectopic p62 expression is sufficient for HCC induction in autophagy-competent liver•p62 exerts its oncogenic activity via NRF2 and mTORC1 but not via ubiquitin binding•p62 promotes survival and expansion of ROS-containing HCC-initiating cells
Umemura et al. employ several mouse models of HCC to demonstrate that p62 facilitates activation of NRF2 and mTORC1 and is essential for HCC initiation. High levels of p62 accumulation in non-tumor liver tissue in early-stage HCC patients undergoing curative ablation correlates with reduced overall survival.
Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found ...that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.
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•p62 levels are reduced in hepatic stellate cells (HSCs) in human HCC samples•Loss of p62 in HSCs results in increased fibrosis, inflammation, and HCC•p62 is critical for VDR:RXR heterodimerization and inhibition of HSC activation•Enhanced HSC activation by p62 loss impairs VDR signaling and promotes HCC
In hepatocellular carcinoma (HCC), p62 is increased in hepatocytes but decreased in hepatic stellate cells (HSCs). Duran et al. show that loss of p62 in HSCs promotes HCC development by reducing the vitamin D receptor (VDR)-RXR interaction, leading to impaired repression of fibrosis and inflammation by VDR.
The signaling adaptor p62 is a critical mediator of important cellular functions, owing to its ability to establish interactions with various signaling intermediaries. Here, we identify raptor as an ...interacting partner of p62. Thus, p62 is an integral part of the mTORC1 complex and is necessary to mediate amino acid signaling for the activation of S6K1 and 4EBP1. p62 interacts in an amino acid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags proteins and favors formation of the active Rag heterodimer that is further stabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation.
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► p62 is a component of mTORC1 complex and not mTORC2 via interaction with raptor ► p62 is required for mTORC1 activation in response to amino acids ► p62 interacts with the Rag GTPases and induces the formation of the active Rag dimer ► p62 mediates mTORC1 recruitment to lysosomes
Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
Since many hepatomegaly-inducing toxicants and ...stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology.
Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.
NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors.
Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
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•Liver p62 accumulation and constitutive NRF2 activation lead to liver lipid buildup, glycogen synthesis and hepatomegaly.•NRF2 activation mediates transcriptional induction of PDGF and EGF receptor ligands that activate AKT.•AKT and tyrosine kinase inhibitors block NRF2-mediated AKT activation and hepatomegaly.•NRF2-AKT signaling is elevated in HSOS- and AIH-related human hepatomegaly.
The ability of cells to respond to changes in nutrient availability is critical for an adequate control of metabolic homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is a central complex ...kinase in these processes. The signaling adaptor p62 binds raptor, and integral component of the mTORC1 pathway. p62 interacts with TNF receptor associated factor 6 (TRAF6) and is required for mTORC1 translocation to the lysosome and its subsequent activation. Here we show that TRAF6 is recruited to and activates mTORC1 through p62 in amino acid-stimulated cells. We also show that TRAF6 is necessary for the translocation of mTORC1 to the lysosomes and that the TRAF6-catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids. TRAF6, through its interaction with p62 and activation of mTORC1, modulates autophagy and is an important mediator in cancer cell proliferation. Interfering with the p62-TRAF6 interaction serves to modulate autophagy and nutrient sensing.
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•TRAF6 is recruited to mTORC1 through p62 in amino acid-activated cells•TRAF6 is required for mTORC1 activation in response to amino acids•TRAF6-catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids•The TRAF6-p62 complex modulates autophagy and cancer cell proliferation
The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels ...were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.
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•p62 levels are reduced in mouse and human tumor stroma•p62 loss in stromal fibroblasts resulted in increased epithelial tumorigenesis•p62 regulates stromal inflammation by mTor/c-Myc metabolic reprogramming•Stromal metabolic reprogramming is essential for IL-6-driven epithelial tumorigenesis
Valencia et al. show that reduced levels of p62 in cancer-associated fibroblasts increase prostate epithelial cell cancer tumorigenesis. They show that p62 modulates stromal cell glucose and amino acid metabolism through an mTORC1/c-Myc pathway, resulting in increased secretion of tumor-promoting IL-6.
Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the ...upregulation of SOX2 is central to this process, which is repressed by protein kinase Cζ (PKCζ). PKCζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1/2 in CAFs impaired the induction of migration and invasion of colon cancer cells, as well as their tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential.
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•PKCζ is lost in the stroma of poor-prognosis mesenchymal human CMS4 CRC•Stromal loss of PKCζ upregulates SOX2 to promote the CAF phenotype•Selective deletion of PKCζ in fibroblast activates the SOX2/SFRP1/2 axis in vivo•Stromal SOX2 negatively correlates with PKCζ and predicts poor survival in CRC
Kasashima et al. describe a molecular mechanism whereby the loss of PKCζ in the stroma upregulates SOX2 to activate the reprogramming of colonic fibroblasts generating a SFRP1/2-expressing CAF population. This population supports epithelial tumor progression, revealing vulnerabilities in mesenchymal CMS4 colorectal cancer.
Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of ...the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.
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•Loss of p62 in the stroma reprograms metabolism to endure glutamine deprivation•Stromal loss of p62 upregulates ATF4 to sustain asparagine-mediated tumor growth•p62 regulates ATF4 stability through ubiquitin-mediated proteasomal degradation•Fibroblast-selective deletion of p62 activates the ATF4-ASNS axis in vivo
Tumors suffer nutrient stress and need to reprogram their metabolism to survive. Linares et al. elucidate a key role for p62 in rewiring the metabolism of tumor stromal fibroblasts to sustain growth of both stromal and epithelial tumor cells, thus making p62 a novel cancer vulnerability point.
Eco-efficiency is currently receiving ever increasing interest as an indicator of sustainability, as it links environmental and economic performances in productive activities. In agriculture these ...indicators and their determinants prove relevant due to the close ties in this activity between the use of often limited natural resources and the provision of basic goods for society. The present paper analyzes eco-efficiency at micro-level, focusing on small-scale family farms as the principal decision-making units (DMUs) of horticulture in southeast Spain, which represents over 30% of fresh vegetables produced in the country. To this end, Data Envelopment Analysis (DEA) framework is applied, computing several combinations of environmental pressures (water usage, phytosanitary contamination, waste management, etc.) and economic value added. In a second stage we analyze the influence of family farms' socio-economic and environmental features on eco-efficiency indicators, as endogenous variables, by using truncated regression and bootstrapping techniques. The results show major inefficiency in aspects such as waste management, among others, while there is relatively minor inefficiency in water usage and nitrogen balance. On the other hand, features such as product specialization, adoption of quality certifications, and belonging to a cooperative all have a positive influence on eco-efficiency. These results are deemed to be of interest to agri-food systems structured on small-scale producers, and they may prove useful to policy-makers as regards managing public environmental programs in agriculture.
•Assessing eco-efficiency and its determinants as indicators of sustainable farming.•Family farms as main decision making units on environmental-economic performance.•Evaluation is carried out by Data Envelopment Analysis and truncated regressions.•Experience, inheritance and cooperative integration of farms can reduce inefficiencies.•R&D proactivity, quality controls and environmental innovation improve eco-efficiency.
Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in ...sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity.
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