المؤلفون: Chen, N, Eritja, N, Lock, R, Debnath, Jayanta

المصدر: Oncogene. 32(20)

مصطلحات موضوعية: Adaptor Proteins, Signal Transducing, Apoptosis, Autophagy, Cell Culture Techniques, Cell Line, Cell Proliferation, Cell Transformation, Neoplastic, Humans, Hydroxychloroquine, Lysosomes, Mechanistic Target of Rapamycin Complex 1, Mitogen-Activated Protein Kinases, Multiprotein Complexes, Mutation, Phosphatidylinositol 3-Kinase, Sequestosome-1 Protein, Sirolimus, TOR Serine-Threonine Kinases

الوصف: Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the phosphatidylinositol 3-kinase(PI3K)/Akt/mammalian target of rapamycin pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor-suppressive and -promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, autophagy gene depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, overexpression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the extracellular signal-related kinase/mitogen-activated protein kinase pathway and to promote epidermal growth factor-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4m91q50wTest
https://escholarship.org/content/qt4m91q50w/qt4m91q50w.pdfTest

المؤلفون: Nami McCarty, Lin Lyu, Tsung-Chin Lin

المصدر: Oncogene

مصطلحات موضوعية: 0301 basic medicine, Genome instability, Cancer Research, DNA End-Joining Repair, DNA Repair, Cell Survival, DNA damage, DNA repair, Filamins, Protein degradation, Biology, Radiation Tolerance, Genomic Instability, Article, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Radiation, Ionizing, Sequestosome-1 Protein, Autophagy, Genetics, Humans, FLNA, Molecular Biology, Intracellular Signaling Peptides and Proteins, Recombinational DNA Repair, Cell biology, Protein Transport, 030104 developmental biology, Gene Expression Regulation, Cytoplasm, 030220 oncology & carcinogenesis, Cancer cell, Protein Multimerization, Multiple Myeloma, Tumor Suppressor p53-Binding Protein 1, DNA Damage, Protein Binding

الوصف: Cancer cells show increases in protein degradation pathways, including autophagy, during progression to meet the increased protein degradation demand and support cell survival. On the other hand, reduced autophagy activity during aging is associated with a reduced DNA damage response and increased genomic instability. Therefore, it is a puzzling how DNA repair can be increased in cancer cells that are resistant to chemotherapies or during progression when autophagy activity is intact or increased. We discovered that tripartite motif containing 44 (TRIM44) is a pivotal element regulating the DNA damage response in cancer cells with intact autophagy. TRIM44 deubiquitinates p62, an autophagy substrate, which leads to its oligomerization. This prevents p62 localization to the nucleus upon irradiation. Increased cytoplasmic retention of p62 by TRIM44 prevents the degradation of FLNA and 53BP1, which increases DNA damage repair. Together, our data support TRIM44 a potential therapeutic target for therapy-resistant tumor cells with intact autophagy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b6564a4e1cb7cdf845874f2d6102fc8cTest
https://doi.org/10.1038/s41388-021-01890-7Test

المؤلفون: Feng Shi, Bei-Qing Pan, Yu Zhang, Yan Cai, Zhi-Hui Xie, Ming-Rong Wang, Li Shang, Xin Xu, Jia-Jie Hao, Chao Shi, Yan-Yi Jiang

المصدر: Oncogene. 37:3260-3274

مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Esophageal Neoplasms, Apoptosis, Biology, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Sequestosome 1, Downregulation and upregulation, Cell Line, Tumor, Sequestosome-1 Protein, Genetics, SKP2, medicine, Animals, Humans, education, S-Phase Kinase-Associated Proteins, Molecular Biology, Protein Kinase C, Mice, Inbred BALB C, education.field_of_study, medicine.diagnostic_test, Protein Stability, Ubiquitination, Xenograft Model Antitumor Assays, Culture Media, Squamous carcinoma, Gene Expression Regulation, Neoplastic, Isoenzymes, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Female, Esophageal Squamous Cell Carcinoma, Signal transduction

الوصف: Esophageal squamous cell carcinoma (ESCC) is one of the malignancies in digestive system, with a low 5-year survival rate. We previously revealed that Sequestosome 1 (SQSTM1/p62) protein levels were upregulated in ESCC tissues. However, it is unclear about the function of p62 and the underlying mechanism. Here, we used immunofluorescence and immunohistochemistry to investigate the expression of p62 in ESCC. Western blotting, quantitative RT-PCR, colony formation assay, flow cytometry, immunoprecipitation and xenograft tumor assay were used to analyze the role of p62 in vitro and vivo. Here, we showed that p62 serves as a regulator of cell apoptosis under serum starvation condition in ESCC cells. Through activating the protein kinase C iota (PKCiota)-S-phase kinase-associated protein 2 (SKP2) signaling pathway, p62 enhances cell apoptosis resistance and colony formation in vitro and tumor growth in mouse models. Through interaction with the domains PB1, p62 upregulated the expression of PKCiota and then depressed the ubiquitin-mediated proteasomal degradation of SKP2. p62-silencing combined with a PKCiota inhibitor ATM significantly enhanced cell apoptosis and inhibited cell survival. Immunohistochemical analysis revealed a positive association between the expression of p62 and SKP2 in primary ESCC tissues. And importantly, p62 presented a markedly cytoplasmic translocation in cancerous cells, including in 16 (30.76%) tumors at stage T1, as compared with its nuclear location in normal esophageal epithelial cells. In summary, p62 plays an anti-apoptotic role in ESCC cells via stabilizing SKP2 under serum starvation condition. These data suggest that p62 might be an early biomarker and a candidate therapeutic target of ESCC.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9232aad8635448994f41cb2ab6a985f9Test
https://doi.org/10.1038/s41388-018-0217-0Test

المؤلفون: Xingyu Jiang, Yun-Song Yang, Zhaoyun Zhang, Z Qian, Fanghui Sun, Zhaohu Lin, Huijuan Liu, Xuefeng Liu, Kou Xinhui, Lan Jiang, Yan Bao, Xiayu Li

المصدر: Oncogene

مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Small interfering RNA, NF-E2-Related Factor 2, Lipid kinase activity, Biology, Caspase 8, medicine.disease_cause, Mice, 03 medical and health sciences, Neoplasms, Sequestosome-1 Protein, Genetics, medicine, Animals, Humans, Phosphorylation, Molecular Biology, Mice, Inbred BALB C, Gene knockdown, Kinase, fungi, Class III Phosphatidylinositol 3-Kinases, Molecular biology, Cell biology, Protein Kinase C-delta, HEK293 Cells, 030104 developmental biology, Cancer cell, Disease Progression, MCF-7 Cells, Female, Original Article, Carcinogenesis

الوصف: Vps34, a class III PtdIns3 lipid kinase involved in the control of both autophagic and endocytic systems, has been studied extensively in numerous fundamental cellular processes. Accumulating evidence indicates that Vps34 may also contribute to the development and progression of human cancers. However, the mechanism of Vps34 in tumorigenesis remains elusive. Here, we report an unanticipated role of Vps34 in the activation of p62 for cancer development. We identified that Vps34 is a transcriptional activator of p62 through competition of Nrf2 (nuclear factor erythroid 2-related factor 2) for Keap1 binding. Vps34 augments the association of PKC-δ with p62 for its phosphorylation at Serine 349, which leads to positive feedback on the Nrf2-dependent transcription of oncogenes. Additionally, we found that the expression of Vps34 is correlated with the tumorigenic activity of human breast cancer cells. Normally inactive in breast cancer, caspase 8 can cleave Vps34 at residue D285, which directly abolished its lipid kinase activity and dramatically altered cell invasion potential, colony formation, as well as tumorigenesis in orthotopic engraftments in mice. The cleavage at D285 blocks expression of LC3-II, Nrf2 and subsequently, p62, in addition to blocking tumor growth, indicating that the intact structure of Vps34 is essential for its activity. Moreover, either knockout of PKC-δ or knockdown of p62 by small interfering RNA in MCF-7 cells abrogates Vps34-dependent tumor growth. Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-δ- activation of p62.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fc1fc58de91996d0500ab5d73750501aTest
https://doi.org/10.1038/onc.2017.295Test

المؤلفون: Jianping Wu, Yuanzhi Lao, Zhibin Hu, Wei Xu, Jie He, Lin Liu, Yaou Zhang, Gang Wan, Zhilin Li, Hao Hu, Naihan Xu, X Wei, Xuan Luo, Wei Xie

المصدر: Oncogene

مصطلحات موضوعية: 0301 basic medicine, Genome instability, Cancer Research, DNA damage, Autophagy-Related Proteins, Mice, Nude, Breast Neoplasms, Tumor initiation, Biology, medicine.disease_cause, Genomic Instability, 03 medical and health sciences, Mice, Breast cancer, Sequestosome-1 Protein, Genetics, medicine, Autophagy, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, Molecular Biology, ATG16L1, Mice, Inbred BALB C, BECN1, medicine.disease, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, Cell Transformation, Neoplastic, Cancer research, Original Article, Beclin-1, Female, Carcinogenesis, DNA Damage

الوصف: Gene expression analysis of The Cancer Genome Atlas (TCGA) breast cancer data set show that miR-20a is upregulated in human breast cancer, especially in triple-negative subtype. Gene Set Enrichment Analysis suggests that miR-20a expression negatively correlates with the autophagy/lysosome pathway. We report here that miR-20a inhibits the basal and nutrient starvation-induced autophagic flux and lysosomal proteolytic activity, increases intracellular reactive oxygen species levels and DNA damage response by targeting several key regulators of autophagy, including BECN1, ATG16L1 and SQSTM1. Re-introduction of exogenous BECN1, ATG16L1 or SQSTM1 reverses the inhibitory effect of miR-20a on autophagy and decreases DNA damage. A negative correlation between miR-20a and its target genes is observed in breast cancer tissues. Lower levels of BECN1, ATG16L1 and SQSTM1 are more common in triple-negative cancers than in other subtypes. High levels of miR-20a also associate with higher frequency of copy-number alterations and DNA mutations in breast cancer patients. Further studies in a xenograft mouse model show that miR-20a promotes tumor initiation and tumor growth. Collectively, these findings suggest that miR-20a-mediated autophagy defect might be a new mechanism underlying the oncogenic function of miRNA during breast tumorigenesis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3b1745152a5eb7371f1044d0bb5cd95Test
http://europepmc.org/articles/PMC5658668Test

المؤلفون: Petri, Pölönen, Ashik, Jawahar Deen, Hanna M, Leinonen, Henna-Kaisa, Jyrkkänen, Suvi, Kuosmanen, Mimmi, Mononen, Ashish, Jain, Tomi, Tuomainen, Sanna, Pasonen-Seppänen, Jaana M, Hartikainen, Arto, Mannermaa, Matti, Nykter, Pasi, Tavi, Terje, Johansen, Merja, Heinäniemi, Anna-Liisa, Levonen

المصدر: Oncogene. 38(50)

مصطلحات موضوعية: Feedback, Physiological, Male, Epithelial-Mesenchymal Transition, Kelch-Like ECH-Associated Protein 1, NF-E2-Related Factor 2, Progression-Free Survival, Gene Expression Regulation, Neoplastic, Oxidative Stress, Sequestosome-1 Protein, Human Umbilical Vein Endothelial Cells, Humans, Female, Neoplasm Invasiveness, Glioblastoma, Cell Proliferation, Protein Binding, Signal Transduction

الوصف: Accumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote cancer cell proliferation and chemoresistance. The mechanisms of Nrf2 dysregulation and functions in cancer have not been fully characterized. Here, we jointly analyzed the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Atlas (TCGA) multi-omics data in order to identify cancer types where Nrf2 activation is present. We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype, and uncover several different mechanisms contributing to increased Nrf2 activity. Importantly, we identified a positive feedback loop between SQSTM1/p62 and Nrf2 as a mechanism for activation of the Nrf2 pathway. We also show that autophagy and serine/threonine signaling regulates p62 mediated Keap1 degradation. Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition. Finally, Nrf2 activity was associated with decreased progression free survival in TCGA GBM patient samples, suggesting that treatments have limited efficacy if this transcription factor is overactivated. Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance. Thus, Nrf2 activation could be used as a surrogate prognostic marker in mesenchymal subtype GBMs. Furthermore, strategies aiming at either inhibiting Nrf2 or exploiting Nrf2 hyperactivity for targeted gene therapy may provide novel treatment options for this subset of GBM.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::18abe12f6472c3053b012770dce130b7Test
https://pubmed.ncbi.nlm.nih.gov/31444413Test

المؤلفون: Xu, L-Z, Li, S-S, Zhou, W, Kang, Z-J, Zhang, Q-X, Kamran, M, Xu, J, Liang, D-P, Wang, C-L, Hou, Z-J, Wan, X-B, Wang, H-J, Lam, E W-F, Zhao, Z-W, Liu, Q

المصدر: Oncogene

مصطلحات موضوعية: RNA Stability, Breast Neoplasms, Middle Aged, Prognosis, Up-Regulation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Mice, MicroRNAs, Cell Line, Tumor, Sequestosome-1 Protein, MCF-7 Cells, Neoplastic Stem Cells, Animals, Humans, Original Article, Female, RNA, Messenger, Neoplasm Transplantation

الوصف: Aberrant p62 overexpression has been implicated in breast cancer development. Here, we found that p62 expression was elevated in breast cancer stem cells (BCSCs), including CD44+CD24− fractions, mammospheres, ALDH1+ populations and side population cells. Indeed, short-hairpin RNA (shRNA)-mediated knockdown of p62 impaired breast cancer cells from self-renewing under anchorage-independent conditions, whereas ectopic overexpression of p62 enhanced the self-renewal ability of breast cancer cells in vitro. Genetic depletion of p62 robustly inhibited tumor-initiating frequencies, as well as growth rates of BCSC-derived tumor xenografts in immunodeficient mice. Consistently, immunohistochemical analysis of clinical breast tumor tissues showed that high p62 expression levels were linked to poorer clinical outcome. Further gene expression profiling analysis revealed that p62 was positively correlated with MYC expression level, which mediated the function of p62 in promoting breast cancer stem-like properties. MYC mRNA level was reduced upon p62 deletion by siRNA and increased with p62 overexpression in breast cancer cells, suggesting that p62 positively regulated MYC mRNA. Interestingly, p62 did not transactivate MYC promoter. Instead, p62 delayed the degradation of MYC mRNA by repressing the expression of let-7a and let-7b, thus promoting MYC mRNA stabilization at the post-transcriptional level. Consistently, let-7a and let-7b mimics attenuated p62-mediated MYC mRNA stabilization. Together, these findings unveiled a previously unappreciated role of p62 in the regulation of BCSCs, assigning p62 as a promising therapeutic target for breast cancer treatments.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::0bb72cfaa3a616e39bce5ff27a39d548Test
http://europepmc.org/articles/PMC5269535Test

المؤلفون: Jenny P.-Y. Ting, Yu Lei, Jing Li, Haitao Wen, Yang Liu, Sumita Trivedi, Hongjiao Ouyang, Linhai Cong, Benjamin A. Kansy, Robert L. Ferris

المصدر: Oncogene

مصطلحات موضوعية: 0301 basic medicine, Sequestosome-1 Protein, autophagy, Cancer Research, EGFR, Medizin, Cetuximab, Peptide Elongation Factor Tu, Biology, Article, Mitochondrial Proteins, 03 medical and health sciences, Growth factor receptor, Cell Line, Tumor, Genetics, medicine, Humans, NLRX1, Molecular Targeted Therapy, Epidermal growth factor receptor, Molecular Biology, EGFR inhibitors, Squamous Cell Carcinoma of Head and Neck, Autophagy, TUFM, Antibodies, Monoclonal, Cell cycle, medicine.disease, Head and neck squamous-cell carcinoma, 3. Good health, Cell biology, ErbB Receptors, 030104 developmental biology, Head and Neck Neoplasms, Carcinoma, Squamous Cell, biology.protein, head and neck cancer, medicine.drug

الوصف: Epidermal growth factor receptor (EGFR)-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1 (nucleotide-binding, lots of leucine-rich repeats-containing protein member X1)-TUFM (Tu translation elongation factor mitochondrial) protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a17cf7d79b36838d050d75bdd3dbd15dTest
https://doi.org/10.1038/onc.2016.11Test

المؤلفون: X Cai-McRae, H Zhong, Vassiliki Karantza

المصدر: Oncogene. 34:2968-2977

مصطلحات موضوعية: Cancer Research, Cell Survival, NF-E2-Related Factor 2, Receptor, ErbB-2, Transgene, Cell Culture Techniques, Mice, Nude, Breast Neoplasms, Mice, Transgenic, Mice, Sequestosome 1, Cell Line, Tumor, Sequestosome-1 Protein, Genetics, Animals, Humans, PTEN, Tensin, education, Molecular Biology, Protein kinase B, Adaptor Proteins, Signal Transducing, education.field_of_study, Kelch-Like ECH-Associated Protein 1, biology, Intracellular Signaling Peptides and Proteins, PTEN Phosphohydrolase, Wnt signaling pathway, Signal transducing adaptor protein, Cell Transformation, Neoplastic, MCF-7 Cells, biology.protein, Cancer research, Female, Signal transduction, Neoplasm Transplantation, Signal Transduction

الوصف: Previous studies have shown that increased levels of the adaptor protein Sequestosome 1/p62 are observed in human breast cancers and significantly correlate with HER2 overexpression. However, the role of p62 in the pathophysiology of HER2-induced mammary tumorigenesis has not yet been investigated. In this study, we report that p62 facilitates HER2-mediated cell survival in both two-dimensional and three-dimensional cell culture and that HER2-induced cellular transformation requires p62, as well as NRF2, which is known to become stabilized by its release from Kelch-like ECH-associated protein 1 (KEAP1) via p62-KEAP1 interaction. In agreement with these results, genetic ablation of p62 delays HER2-induced mammary tumorigenesis in tumor cell allografts in nude mice, and in MMTV-Neu transgenic mice. We also report that ablation of p62 impairs AKT and β-catenin activation in association with PTEN (phosphatase and tensin homolog deleted on chromosome ten) accumulation, both in vitro and in vivo. Further in vivo studies suggest that loss of p62 also impairs NF-κB and NRF2 activation. Collectively, our results provide compelling evidence that p62 contributes to HER2-induced mammary tumorigenesis through multiple signaling pathways, including the PTEN/phosphoinositide-3-kinase/AKT axis, WNT/β-catenin signaling, the NF-κB pathway and the NRF2-KEAP1 axis, and offer novel insights into the potential role of p62 in the regulation of the tumor suppressor PTEN.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4f78838383840d47bf17c7155fb2edc7Test
https://doi.org/10.1038/onc.2014.244Test

المؤلفون: X. Zhang, Peter German, Mianen Sun, Jun Yao, Jiangwei Zhang, Eric Jonasch, Nizar M. Tannir, D. Jonasch, Gordon B. Mills, Lijun Zhou, N. T. Eissa, Eleni Efstathiou, Anh Hoang, Shanshan Bai, Durga Nand Tripathi, Yixiang Xu, Xian De Liu, Zhiyong Ding, Cheryl L. Walker, Claudio J. Conti

المصدر: Oncogene

مصطلحات موضوعية: Sequestosome-1 Protein, autophagy, Cancer Research, Programmed cell death, Ubiquitin-activating enzyme, Ubiquitin-Activating Enzymes, Biology, Kidney, medicine.disease_cause, Autophagy-Related Protein 7, Article, Cell Line, Tumor, VHL, Basic Helix-Loop-Helix Transcription Factors, Genetics, medicine, Humans, RNA, Small Interfering, Carcinoma, Renal Cell, Molecular Biology, Transcription factor, Adaptor Proteins, Signal Transducing, p62, Autophagy, Membrane Proteins, RCC, Kidney Neoplasms, Cell biology, Ubiquitin ligase, Cell Transformation, Neoplastic, HEK293 Cells, proteasome, Von Hippel-Lindau Tumor Suppressor Protein, biology.protein, Beclin-1, RNA Interference, Apoptosis Regulatory Proteins, HIF2α, Carcinogenesis

الوصف: Autophagy is a conserved process involved in lysosomal degradation of protein aggregates and damaged organelles. The role of autophagy in cancer is a topic of intense debate, and the underlying mechanism is still not clear. The hypoxia inducible factor 2α (HIF2α), an oncogenic transcription factor implicated in renal tumorigenesis, is known to be degraded by the ubiquitin-proteasome system (UPS). Here we report that HIF2α is in part constitutively degraded by autophagy. HIF2α interacts with autophagy-lysosome system components. Inhibition of autophagy increases HIF2α, while induction of autophagy decreases HIF2α. The E3 ligase von Hippel Lindau (VHL) and autophagy receptor protein p62 are required for autophagic degradation of HIF2α. There is a compensatory interaction between the UPS and autophagy in HIF2α degradation. Autophagy inactivation redirects HIF2α to proteasomal degradation, while proteasome inhibition induces autophagy and increases the HIF2α-p62 interaction. Importantly, clear cell renal cell carcinoma (ccRCC) is frequently associated with mono-allelic loss and/or mutation of autophagy related gene ATG7, and low expression level of autophagy genes correlates with ccRCC progression. The protein levels of ATG7 and beclin 1 are also reduced in ccRCC tumors. This study indicates that autophagy plays an anticancer role in ccRCC tumorigenesis, and suggests that constitutive autophagic degradation of HIF2α is a novel tumor suppression mechanism.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::282ce385be3a62860f02561cc2dbcf2cTest
https://doi.org/10.1038/onc.2014.199Test