Loss of the Tumor Suppressor HACE1 Contributes to Cancer Progression

Author(s): Jun-Chen Li , Xing Chang , Yang Chen , Xin-Zhe Li , Xiang-Lian Zhang , Shi-Ming Yang , Chang-Jiang Hu* , Hao Zhang* .

Journal Name: Current Drug Targets

Volume 20 , Issue 10 , 2019

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Graphical Abstract:


HACE1 belongs to the family of HECT domain-containing E3 ligases, which plays an important role in the occurrence, invasion and metastatic process in many human malignancies. HACE1 is a tumor suppressor gene that is reduced in most cancer tissues compared to adjacent normal tissue. The loss or knocking out of HACE1 leads to enhanced tumor growth, invasion, and metastasis; in contrast, the overexpression of HACE1 can inhibit the development of tumors. Hypermethylation reduces the expression of HACE1, thereby promoting tumor development. HACE1 can inhibit the development of inflammation or tumors via the ubiquitination pathway. Therefore, HACE1 may be a potential therapeutic target, providing new strategies for disease prevention and treatment.

Keywords: HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1), tumor suppressor, methylation, ubiquitylation, RAC1.

Zhang L, Anglesio MS, O’Sullivan M, et al. The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nat Med 2007; 13(9): 1060-9.
Chen YL, Li DP, Jiang HY, et al. Overexpression of HACE1 in gastric cancer inhibits tumor aggressiveness by impeding cell proliferation and migration. Cancer Med 2018; 7(6): 2472-84.
Hibi K, Sakata M, Sakuraba K, et al. Aberrant methylation of the HACE1 gene is frequently detected in advanced colorectal cancer. Anticancer Res 2008; 28(3A): 1581-4.
Zhou Z, Zhang HS, Zhang ZG, et al. Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1. J Cell Physiol 2019; 234(6): 9663-72.
Anglesio MS, Evdokimova V, Melnyk N, et al. Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms’ tumor versus normal kidney. Hum Mol Genet 2004; 13(18): 2061-74.
Bernassola F, Karin M, Ciechanover A, Melino G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 2008; 14(1): 10-21.
Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 2009; 10(6): 398-409.
Karube K, Nakagawa M, Tsuzuki S, et al. Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. Blood 2011; 118(12): 3195-204.
Stewénius Y, Jin Y, Ora I, et al. High-resolution molecular cytogenetic analysis of Wilms tumors highlights diagnostic difficulties among small round cell kidney tumors. Genes Chromosomes Cancer 2008; 47(10): 845-52.
Liu Z, Chen P, Gao H, et al. Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression. Cancer Cell 2014; 26(1): 106-20.
Zhang W, Wu KP, Sartori MA, et al. System-wide modulation of hect e3 ligases with selective ubiquitin variant probes. Mol Cell 2016; 62(1): 121-36.
Sluimer J, Distel B. Regulating the human HECT E3 ligases. Cell Mol Life Sci 2018; 75(17): 3121-41.
de Bie P, Ciechanover A. Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms. Cell Death Differ 2011; 18(9): 1393-402.
Gao LM, Zhao S, Liu WP, et al. clinicopathologic characterization of aggressive natural killer cell leukemia involving different tissue sites. Am J Surg Pathol 2016; 40(6): 836-46.
Sakata M, Kitamura YH, Sakuraba K, et al. Methylation of HACE1 in gastric carcinoma. Anticancer Res 2009; 29(6): 2231-3.
Huang WY, Hsu SD, Huang HY, et al. MethHC: a database of DNA methylation and gene expression in human cancer. Nucleic Acids Res 2015; 43(Database issue): D856-61.
Vidal E, Sayols S, Moran S, et al. A DNA methylation map of human cancer at single base-pair resolution. Oncogene 2017; 36(40): 5648-57.
Dor Y, Cedar H. Principles of DNA methylation and their implications for biology and medicine. Lancet 2018; 392(10149): 777-86.
Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta 2013; 424: 53-65.
Satija YK, Bhardwaj A, Das S. A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer. Int J Cancer 2013; 133(12): 2759-68.
Hurst JH, Dohlman HG. Dynamic ubiquitination of the mitogen-activated protein kinase kinase (MAPKK) Ste7 determines mitogen-activated protein kinase (MAPK) specificity. J Biol Chem 2013; 288(26): 18660-71.
Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem 2009; 78: 399-434.
Maniaci C, Hughes SJ, Testa A, et al. Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation. Nat Commun 2017; 8(1): 830.
Steeg PS. Targeting metastasis. Nat Rev Cancer 2016; 16(4): 201-18.
Heasman SJ, Ridley AJ. Mammalian Rho GTPases: New insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 2008; 9(9): 690-701.
Abo A, Pick E, Hall A, et al. Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature 1991; 353(6345): 668-70.
Payapilly A, Malliri A. Compartmentalisation of RAC1 signalling. Curr Opin Cell Biol 2018; 54: 50-6.
Marei H, Carpy A, Woroniuk A, et al. Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration. Nat Commun 2016; 7: 10664.
MRF R, Ansor NM, Kousi M, et al. RAC1 Missense mutations in developmental disorders with diverse phenotypes. Am J Hum Genet 2017; 101(3): 466-77.
Choudhari R, Minero VG, Menotti M, et al. Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice. Blood 2016; 127(10): 1297-306.
Bid HK, Roberts RD, Manchanda PK, Houghton PJ. RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther 2013; 12(10): 1925-34.
Daugaard M, Nitsch R, Razaghi B, et al. Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes. Nat Commun 2013; 4: 2180.
Andrio E, Lotte R, Hamaoui D, et al. Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation. Sci Rep 2017; 7: 44779.
Sosa MS, Lopez-Haber C, Yang C, et al. Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol Cell 2010; 40(6): 877-92.
Torrino S, Visvikis O, Doye A, et al. The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1. Dev Cell 2011; 21(5): 959-65.
Castillo-Lluva S, Tan CT, Daugaard M, Sorensen PH, Malliri A. The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation. Oncogene 2013; 32(13): 1735-42.
Goka ET, Lippman ME. Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression. Oncogene 2015; 34(42): 5395-405.
Salami J, Crews CM. Waste disposal-An attractive strategy for cancer therapy. Science 2017; 355(6330): 1163-7.
Kim J, Kim J, Bae JS. ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med 2016; 48(11)e269
Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82(1): 47-95.
Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007; 87(1): 245-313.
Hüttemann M, Lee I, Grossman LI, Doan JW, Sanderson TH. Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease. Adv Exp Med Biol 2012; 748: 237-64.
Cetinbas N, Daugaard M, Mullen AR, et al. Loss of the tumor suppressor Hace1 leads to ROS-dependent glutamine addiction. Oncogene 2015; 34(30): 4005-10.
Yu RY, Xing L, Cui PF, et al. Regulating the Golgi apparatus by co-delivery of a COX-2 inhibitor and Brefeldin A for suppression of tumor metastasis. Biomater Sci 2018; 6(8): 2144-55.
Tang D, Xiang Y, De Renzis S, et al. The ubiquitin ligase HACE1 regulates Golgi membrane dynamics during the cell cycle. Nat Commun 2011; 2: 501.
Wang Y, Satoh A, Warren G, Meyer HH, Wang Y. VCIP135 acts as a deubiquitinating enzyme during p97-p47-mediated reassembly of mitotic Golgi fragments. J Cell Biol 2004; 164(7): 973-8.
Lachance V, Degrandmaison J, Marois S, et al. Ubiquitylation and activation of a Rab GTPase is promoted by a β2AR-HACE1 complex. J Cell Sci 2014; 127(Pt 1): 111-23.
Diaz-Corrales FJ, Asanuma M, Miyazaki I, Ogawa N. Rotenone induces disassembly of the Golgi apparatus in the rat dopaminergic neuroblastoma B65 cell line. Neurosci Lett 2004; 354(1): 59-63.
Krishnan V, Bane SM, Kawle PD, Naresh KN, Kalraiya RD. Altered melanoma cell surface glycosylation mediates organ specific adhesion and metastasis via lectin receptors on the lung vascular endothelium. Clin Exp Metastasis 2005; 22(1): 11-24.
Roberts RF, Tang MY, Fon EA, Durcan TM. Defending the mitochondria: The pathways of mitophagy and mitochondrial-derived vesicles. Int J Biochem Cell Biol 2016; 79: 427-36.
Grattagliano I, Russmann S, Diogo C, et al. Mitochondria in chronic liver disease. Curr Drug Targets 2011; 12(6): 879-93.
Kalyanaraman B, Cheng G, Hardy M, et al. A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds. Redox Biol 2018; 14: 316-27.
Ferreira IL, Resende R, Ferreiro E, Rego AC, Pereira CF. Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets 2010; 11(10): 1193-206.
Xiao M, Zhong H, Xia L, Tao Y, Yin H. Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria. Free Radic Biol Med 2017; 111: 316-27.
Mah LY, Ryan KM. Autophagy and cancer. Cold Spring Harb Perspect Biol 2012; 4(1)a008821
White E. The role for autophagy in cancer. J Clin Invest 2015; 125(1): 42-6.
White E, Karp C, Strohecker AM, Guo Y, Mathew R. Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol 2010; 22(2): 212-7.
Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, Inflammation, and Immunity: a troika governing cancer and its treatment. Cell 2016; 166(2): 288-98.
Farré JC, Subramani S. Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat Rev Mol Cell Biol 2016; 17(9): 537-52.
Wild P, Farhan H, McEwan DG, et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 2011; 333(6039): 228-33.
Herhaus L, Dikic I. Expanding the ubiquitin code through post-translational modification. EMBO Rep 2015; 16(9): 1071-83.
Richter B, Sliter DA, Herhaus L, et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci USA 2016; 113(15): 4039-44.
Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137(6): 1062-75.
Kruppa AJ, Kishi-Itakura C, Masters TA, et al. Myosin VI-dependent actin cages encapsulate parkin-positive damaged mitochondria. Dev Cell 2018; 44(4): 484-499.e6.
Hewitt G, Korolchuk VI. Repair, reuse, recycle: the expanding role of autophagy in genome maintenance. Trends Cell Biol 2017; 27(5): 340-51.
Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell 2014; 157(1): 65-75.
Mohammad RM, Muqbil I, Lowe L, et al. Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 2015; 35(Suppl.): S78-S103.
Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature 2015; 517(7534): 311-20.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007; 35(4): 495-516.
Newton K. RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends Cell Biol 2015; 25(6): 347-53.
Tortola L, Nitsch R. MJM B, et al. The Tumor Suppressor hace1 is a critical regulator of TNFR1-mediated cell fate. Cell Rep 2016; 15(7): 1481-92.
Su Z, Yang Z, Xie L, DeWitt JP, Chen Y. Cancer therapy in the necroptosis era. Cell Death Differ 2016; 23(5): 748-56.
Strilic B, Yang L, Albarrán-Juárez J, et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 2016; 536(7615): 215-8.
Zeh HJ, Lotze MT. Addicted to death: invasive cancer and the immune response to unscheduled cell death. J Immunother 2005; 28(1): 1-9.
Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 2004; 4(8): 641-8.
Antonio N, Bønnelykke-Behrndtz ML, Ward LC, et al. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J 2015; 34(17): 2219-36.
Rivera MN, Haber DA. Wilms’ tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer 2005; 5(9): 699-712.
Rivera MN, Kim WJ, Wells J, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 2007; 315(5812): 642-5.
Jia W, Deng Z, Zhu J, et al. Association between hace1 gene polymorphisms and wilms’ tumor risk in a chinese population. Cancer Invest 2017; 35(10): 633-8.
Diskin SJ, Capasso M, Schnepp RW, et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet 2012; 44(10): 1126-30.
Slade I, Stephens P, Douglas J, et al. Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies HACE1 as a putative Wilms tumour susceptibility gene. J Med Genet 2010; 47(5): 342-7.
De Carvalho DD, Sharma S, You JS, et al. DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 2012; 21(5): 655-67.
Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet 2016; 388(10060): 2654-64.
Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol 2017; 14(8): 467-78.
DeNardo DG, Johansson M, Coussens LM. Inflaming gastrointestinal oncogenic programming. Cancer Cell 2008; 14(1): 7-9.
Du YC, Oshima H, Oguma K, et al. Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis. Gastroenterology 2009; 137(4): 1346-57.
Zouridis H, Deng N, Ivanova T, et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci Transl Med 2012; 4(156)156ra140
Suzuki H, Gabrielson E, Chen W, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002; 31(2): 141-9.
Orme M, Bianchi K, Meier P. Ubiquitin-mediated regulation of RhoGTPase signalling: IAPs and HACE1 enter the fray. EMBO J 2012; 31(1): 1-2.
Schnelzer A, Prechtel D, Knaus U, et al. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 2000; 19(26): 3013-20.
Laurin M, Huber J, Pelletier A, et al. Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis. Proc Natl Acad Sci USA 2013; 110(18): 7434-9.
Sonoshita M, Itatani Y, Kakizaki F, et al. Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer Discov 2015; 5(2): 198-211.
Thent ZC, Zaidun NH, Azmi MF, et al. Is Metformin a therapeutic paradigm for colorectal cancer: insight into the molecular pathway. Curr Drug Targets 2017; 18(6): 734-50.
Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017; 66(4): 683-91.
Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 2011; 8(12): 686-700.
Song L, Li Y. The role of stem cell DNA methylation in colorectal carcinogenesis. Stem Cell Rev 2016; 12(5): 573-83.
Kotelevets L, Walker F, Mamadou G, et al. The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression. Oncogene 2018; 37(46): 6054-68.
Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008; 135(4): 1079-99.
Gao ZF, Wu YN, Bai ZT, et al. Tumor-suppressive role of HACE1 in hepatocellular carcinoma and its clinical significance. Oncol Rep 2016; 36(6): 3427-35.
Deng S, Huang C. E3 ubiquitin ligases in regulating stress fiber, lamellipodium, and focal adhesion dynamics. Cell Adhes Migr 2014; 8(1): 49-54.
Jiang L, Gu ZH, Yan ZX, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet 2015; 47(9): 1061-6.
Sako N, Dessirier V, Bagot M, Bensussan A, Schmitt C. HACE1, a potential tumor suppressor gene on 6q21, is not involved in extranodal natural killer/T-cell lymphoma pathophysiology. Am J Pathol 2014; 184(11): 2899-907.
Huang Y, de Reyniès A, de Leval L, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood 2010; 115(6): 1226-37.
Huang Y, de Leval L, Gaulard P. Molecular underpinning of extranodal NK/T-cell lymphoma. Best Pract Res Clin Haematol 2013; 26(1): 57-74.
Küçük C, Hu X, Iqbal J, et al. HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms. Am J Pathol 2013; 182(1): 49-55.
El-Hachem N, Habel N, Naiken T, et al. Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells. Cell Death Differ 2018; 25(11): 2010-22.
Ma J, Guo W, Li C. Ubiquitination in melanoma pathogenesis and treatment. Cancer Med 2017; 6(6): 1362-77.
Bouzelfen A, Kora H, Alcantara M, et al. Heterogeneous epigenetic regulation of HACE1 in Burkitt- Lymphoma-derived cells. Leuk Res 2017; 60: 53-7.
Miranda TB, Cortez CC, Yoo CB, et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 2009; 8(6): 1579-88.
Lee JK, Kim KC. DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells. Biochem Biophys Res Commun 2013; 438(4): 647-52.
Zhou J, Bi C, Cheong LL, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood 2011; 118(10): 2830-9.
Kitagawa K, Kitagawa M. The SCF ubiquitin ligases involved in hematopoietic lineage. Curr Drug Targets 2012; 13(13): 1641-8.
Chandrashekar DS, Bashel B. SAH B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 2017; 19(8): 649-58.
Győrffy B, Surowiak P, Budczies J, Lánczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One 2013; 8(12)e82241
Györffy B, Lanczky A, Eklund AC, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat 2010; 123(3): 725-31.
Yan WL, Shen KY, Tien CY, Chen YA, Liu SJ. Recent progress in GM-CSF-based cancer immunotherapy. Immunother 2017; 9(4): 347-60.
Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol 2016; 34: 539-73.
Malynn BA, Ma A. Ubiquitin makes its mark on immune regulation. Immunity 2010; 33(6): 843-52.

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Year: 2019
Page: [1018 - 1028]
Pages: 11
DOI: 10.2174/1389450120666190227184654
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