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Autophagy-Induced HDAC6 Activity During Hypoxia Regulates Mitochondrial Energy Metabolism Through the β-Catenin/COUP-TFII Axis in Hepatocellular Carcinoma Cells.

ABSTRACT: Hypoxia is one of the main driving forces that results in poor outcomes and drug resistance in hepatocellular carcinoma (HCC). As the critical cellular oxygen sensor, mitochondria respond to hypoxic stress by sending retrograde signals to the nucleus that initiate adaptive metabolic responses and maintain the survival of HCC cells. Increasing evidence suggested autophagy contributes to sustain mitochondrial metabolic and quality control. Understanding how mitochondria communicate with the nucleus and alter transcription may provide promising targets for HCC treatment. In this study, we found mitochondrial undergoes selective degradation by autophagy under hypoxia. Furthermore, autophagy-activated HDAC6 not only promoted the nuclear translocation of β-catenin but also increased the affinity of β-catenin to the transcription repressor chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TF II), which suppressed mitochondrial oxidative phosphorylation-related genes transcription. Our data showed that autophagy served as a critical mediator of integrating mitochondrial energy metabolism and nuclear transcription. HDAC6 may be a potential target for reducing the survival of HCC cells by interrupting mitochondria-nucleus crosstalk.

SUBMITTER: Yan X

PROVIDER: S-EPMC8636061 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism.

Project description:Adipose tissue development and function play a central role in the pathogenesis and pathophysiology of metabolic syndromes. Here, we show that chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) plays a pivotal role in adipogenesis and energy homeostasis. COUP-TFII is expressed in the early stages of white adipocyte development. COUP-TFII heterozygous mice (COUP-TFII(+/-)) have much less white adipose tissue (WAT) than wild-type mice (COUP-TFII(+/+)). COUP-TFII(+/-) mice display a decreased expression of key regulators for WAT development. Knockdown COUP-TFII in 3T3-L1 cells resulted in an increased expression of Wnt10b, while chromatin immunoprecipitation analysis revealed that Wnt10b is a direct target of COUP-TFII. Moreover, COUP-TFII(+/-) mice have increased mitochondrial biogenesis in WAT, and COUP-TFII(+/-) mice have improved glucose homeostasis and increased energy expenditure. Thus, COUP-TFII regulates adipogenesis by regulating the key molecules in adipocyte development and can serve as a target for regulating energy metabolism.

| S-EPMC2630393 | biostudies-literature

COUP-TFII controls mouse pancreatic ?-cell mass through GLP-1-?-catenin signaling pathways.

Project description:BACKGROUND:The control of the functional pancreatic ?-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how ?-cell mass is determined. METHODOLOGY/PRINCIPAL FINDINGS:Conditional chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-deficient mice were generated and crossed with mice expressing Cre under the control of pancreatic duodenal homeobox 1 (pdx1) gene promoter. Ablation of COUP-TFII in pancreas resulted in glucose intolerance. Beta-cell number was reduced at 1 day and 3 weeks postnatal. Together with a reduced number of insulin-containing cells in the ductal epithelium and normal ?-cell proliferation and apoptosis, this suggests decreased ?-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured ?-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the ?-catenin gene and its target genes such as cyclin D1 and axin 2. Moreover, induction of these genes by glucagon-like peptide 1 (GLP-1) via ?-catenin was impaired in absence of COUP-TFII. The expression of two other target genes of GLP-1 signaling, GLP-1R and PDX-1 was significantly lower in mutant islets compared to control islets, possibly contributing to reduced ?-cell mass. Finally, we demonstrated that COUP-TFII expression was activated by the Wnt signaling-associated transcription factor TCF7L2 (T-cell factor 7-like 2) in human islets and rat ?-cells providing a feedback loop. CONCLUSIONS/SIGNIFICANCE:Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases ?-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the ?-catenin-dependent pathway and its expression is under the control of TCF7L2.

| S-EPMC3265526 | biostudies-literature

COUP-TFII in Health and Disease.

Project description:The nuclear receptors (NRs) belong to a vast family of evolutionary conserved proteins acting as ligand-activated transcription factors. Functionally, NRs are essential in embryogenesis and organogenesis and in adulthood they are involved in almost every physiological and pathological process. Our knowledge of NRs action has greatly improved in recent years, demonstrating that both their expression and activity are tightly regulated by a network of signaling pathways, miRNA and reciprocal interactions. The Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII, NR2F2) is a NR classified as an orphan due to the lack of a known natural ligand. Although its expression peaks during development, and then decreases considerably, in adult tissues, COUP-TFII is an important regulator of differentiation and it is variably implicated in tissues homeostasis. As such, alterations of its expression or its transcriptional activity have been studied and linked to a spectrum of diseases in organs and tissues of different origins. Indeed, an altered COUP-TFII expression and activity may cause infertility, abnormality in the vascular system and metabolic diseases like diabetes. Moreover, COUP-TFII is actively investigated in cancer research but its role in tumor progression is yet to be fully understood. In this review, we summarize the current understanding of COUP-TFII in healthy and pathological conditions, proposing an updated and critical view of the many functions of this NR.

| S-EPMC7016888 | biostudies-literature

Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer.

Project description:Although early detection and treatment of prostate cancer (PCa) improves outcomes, many patients still die of metastatic PCa. Here, we report that metastatic PCa exhibits reduced levels of the microRNAsmiR-101 and miR-27a. These micro-RNAs (miRNAs) negatively regulate cell invasion and inhibit the expression of FOXM1 and CENPF, two master regulators of metastasis in PCa. Interestingly, the repression of FOXM1 and CENPF by these miRNAs occurs through COUP-TFII, a member of the orphan nuclear receptors family. Loss of miR-101 positively correlates with the increase of COUP-TFII-FOXM1-CENPF activity in clinical PCa data sets, implicating clinical relevance of such regulation. Further studies show that COUP-TFII is a critical factor controlling metastatic gene networks to promote PCa metastasis. Most importantly, this miRNA-COUP-TFII-FOXM1-CENPF regulatory axis is also involved in the development of enzalutaminde resistance. Taken together, our findings highlight the contribution of specific miRNAs through the regulation of the COUP-TFII-FOXM1-CENPF cascade in PCa metastasis and drug resistance.

| S-EPMC4848536 | biostudies-literature

COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.

Project description:Wnt signaling through beta-catenin and TCF maintains preadipocytes in an un-differentiated proliferative state; however, the molecular pathway has not been completely defined. By integrating gene expression microarray, chromatin immunoprecipitation-chip, and cell-based experimental approaches, we show that Wnt/beta-catenin signaling activates the expression of COUP-TFII which recruits the SMRT corepressor complex to the first introns located downstream from the first exons of both PPARgamma1 and gamma2 mRNAs. This maintains the local chromatin in a hypoacetylated state and represses PPARgamma gene expression to inhibit adipogenesis. Our experiments define the COUP-TFII/SMRT complex as a previously unappreciated component of the linear pathway that directly links Wnt/beta-catenin signaling to repression of PPARgamma gene expression and the inhibition of adipogenesis.

| S-EPMC2667001 | biostudies-literature

COUP-TFII regulates satellite cell function and muscular dystrophy.

Project description:Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease's pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII-overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD.

| S-EPMC5096817 | biostudies-literature

COUP-TFII controls amygdala patterning by regulating neuropilin expression.

Project description:The development of the progenitor zones in the pallium, lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE) in the subpallium has been well studied; however, so far the role of the caudal ganglionic eminence (CGE), a posterior subpallial domain, in telencephalon patterning remains poorly understood. COUP-TFII, an orphan nuclear receptor, is preferentially expressed in the CGE. We generated COUP-TFII mouse mutants, using Rx-Cre (RxCre;COUP-TFII(F/F)), to study its function in telencephalon development. In these mutants, we found severe defects in the formation of the amygdala complex, including the lateral (LA), basolateral (BLA) and basomedial (BMA) amygdala nuclei. Molecular analysis provided evidence that the migration of CGE-derived Pax6(+) cells failed to settle into the BMA nucleus, owing to reduced expression of neuropilin 1 (Nrp1) and Nrp2, two semaphorin receptors that regulate neuronal cell migration and axon guidance. Our ChIP assays revealed that Nrp1 and Nrp2 genes are the direct targets of COUP-TFII in the telencephalon in vivo. Furthermore, our results showed that the coordinated development between the CGE originated subpallial population (Pax6(+) cells) and pallial populations (Tbr1(+) and Lhx2(+) cells) was essential for patterning the amygdala assembly. Our study presented novel genetic evidence that the caudal ganglionic eminence, a distinct subpallial progenitor zone, contributes cells to the basal telencephalon, such as the BMA nucleus.

| S-EPMC3317968 | biostudies-literature

COUP-TFII expressing interneurons in human fetal forebrain.

Project description:Transcription factor COUP-TFII in rodents is important for migration of cortical interneurons from caudal ganglionic eminence (CGE) to the neocortex. Since in human, unlike in rodents, cortical interneurons have both ganglionic eminence (GE) and dorsal cortical origin, we studied the distribution of COUP-TFII in the human developing neocortex from 9 to 22 gestational weeks. COUP-TFII is expressed at all stages studied in the GE and in various cortical zones, from the proliferative ventricular/subventricular zone (VZ/SVZ) to layer I. Gradients of COUP-TFII expression are present in the GE, with peak expression in the CGE, and in the neocortex, from high expression in the temporal and occipital cortex to moderate in the frontal and dorsal cortex. Double immunofluorescence with ?-aminobutyric acid (GABA), calretinin, or calbindin, established that subpopulations of interneurons express COUP-TFII. A small fraction of COUP-TFII(+) cells are progenitor cells that proliferate in the CGE (3.4 ± 0.3%) and in the cortical VZ/SVZ (1.7 ± 0.1%). In summary, COUP-TFII is expressed in the human fetal forebrain in GABAergic cells, according to its possible role in migration of cortical interneurons. The source of these cells seems to be the CGE and, to a smaller extent, the cortical VZ/SVZ.

| S-EPMC3491767 | biostudies-other

Atrial identity is determined by a COUP-TFII regulatory network.

Project description:Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, the factors that determine these differences remain largely undefined. Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria that exhibit ventricle-like action potentials, increased cardiomyocyte size, and development of extensive T tubules. Changes in atrial characteristics are accompanied by alterations of 2,584 genes, of which 81% were differentially expressed between atria and ventricles, suggesting that a major function of myocardial COUP-TFII is to determine atrial identity. Chromatin immunoprecipitation assays using E13.5 atria identified classic atrial-ventricular identity genes Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a, among many other cardiac genes, as potential COUP-TFII direct targets. Collectively, our results reveal that COUP-TFII confers atrial identity through direct binding and by modulating expression of a broad spectrum of genes that have an impact on atrial development and function.

| S-EPMC3687546 | biostudies-literature

Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure.

Project description:The nuclear receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) is an important coordinator of glucose homeostasis through its function in different organs such as the endocrine pancreas, adipose tissue, skeletal muscle, and liver. Recently we have demonstrated that COUP-TFII expression in the hypothalamus is restricted to a subpopulation of neurons expressing the steroidogenic factor 1 transcription factor, known to play a crucial role in glucose homeostasis. To understand the functional significance of COUP-TFII expression in the steroidogenic factor 1 neurons, we generated hypothalamic ventromedial nucleus-specific COUP-TFII KO mice using the cyclization recombination/locus of X-overP1 technology. The heterozygous mutant mice display insulin hypersensitivity and a leaner phenotype associated with increased energy expenditure and similar food intake. These mutant mice also present a defective counterregulation to hypoglycemia with altered glucagon secretion. Moreover, the mutant mice are more likely to develop hypoglycemia-associated autonomic failure in response to recurrent hypoglycemic or glucopenic events. Therefore, COUP-TFII expression levels in the ventromedial nucleus are keys in the ability to resist the onset of hypoglycemia-associated autonomic failure.

| S-EPMC3600439 | biostudies-literature

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