The equilibrium of tumor suppression: DUBs as active regulators of PTEN
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PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have shown that several deubiquitinating enzymes, including HAUSP/USP7, USP10, USP11, USP13, OTUD3 and Ataxin-3, can remove ubiquitin from ubiquitinated PTEN in cancer-specific contexts and thus reverse ubiquitination-mediated PTEN regulation. Researchers continue to reveal the precise molecular mechanisms by which cancer-specific deubiquitinases of PTEN regulate its roles in the pathobiology of cancer, and new methods of pharmacologically for modulating PTEN deubiquitinases are critical areas of investigation for cancer treatment and prevention. Here, we assess the mechanisms and functions of deubiquitination as a recently appreciated mode of PTEN regulation and review the link between deubiquitinases and PTEN reactivation and its implications for therapeutic strategies.
Abstract
PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have shown that several deubiquitinating enzymes, including HAUSP/USP7, USP10, USP11, USP13, OTUD3 and Ataxin-3, can remove ubiquitin from ubiquitinated PTEN in cancer-specific contexts and thus reverse ubiquitination-mediated PTEN regulation. Researchers continue to reveal the precise molecular mechanisms by which cancer-specific deubiquitinases of PTEN regulate its roles in the pathobiology of cancer, and new methods of pharmacologically for modulating PTEN deubiquitinases are critical areas of investigation for cancer treatment and prevention. Here, we assess the mechanisms and functions of deubiquitination as a recently appreciated mode of PTEN regulation and review the link between deubiquitinases and PTEN reactivation and its implications for therapeutic strategies.
참고문헌 (125)
- Hollander, M. C., "PTEN loss in the continuum of common cancers, rare syndromes and mouse models", Nat. Rev. Cancer, 11, pp.289~301 (2011)
- Salmena, L., "Tenets of PTEN tumor suppression", Cell, 133, pp.403~414 (2008)
- Lee, Y. R., "The functions and regulation of the PTEN tumour suppressor : new modes and prospects", Nat. Rev. Mol. Cell Biol, 19, pp.547~562 (2018)
- Song, M. S., "The functions and regulation of the PTEN tumour suppressor", Nat. Rev. Mol. Cell Biol, 13, pp.283~296 (2012)
- Myers, M. P., "P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase", Proc. Natl Acad. Sci, 94, pp.9052~9057 (1997)
- Gu, T., "CREB is a novel nuclear target of PTEN phosphatase", Cancer Res, 71, pp.2821~2825 (2011)
- Shi, Z., "Ataxin-3 promotes testicular cancer cell proliferation by inhibiting anti-oncogene PTEN", Biochem. Biophys. Res. Commun, 503, pp.391~396 (2018)
- Tamura, M., "PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase", Akt cell survival pathway, 1999, pp.274, 20693~20703
- Wozniak, D. J., "PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer", Nat. Commun, 8, pp.1508~ (2017)
- Zhang, S., "Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways", Nat. Med, 17, pp.461~469 (2011)
- Bassi, C., "Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress", Science, 341, pp.395~399 (2013)
- Shen, W. H., "Essential role for nuclear PTEN in maintaining chromosomal integrity", Cell, 128, pp.157~170 (2007)
- Song, M. S., "Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner", Cell, 144, pp.187~199 (2011)
- Wang, G., "PTEN regulates RPA1 and protects DNA replication forks", Cell Res, 25, pp.1189~1204 (2015)
- Eng, C., "PTEN : one gene, many syndromes", Hum. Mutat, 22, pp.183~198 (2003)
- Di Cristofano, A., "Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse", Nat. Genet, 27, pp.222~224 (2001)
- Di Cristofano, A., "Impaired Fas response and autoimmunity in Pten+", -mice, 1999, pp.285, 2122~2125
- Papa, A., "Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function", Cell, 157, pp.595~610 (2014)
- Alimonti, A., "A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis", J. Clin. Invest, 120, pp.681~693 (2010)
- Chen, Z., "Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis", Nature, 436, pp.725~730 (2005)
- Berger, A. H., "A continuum model for tumour suppression", Nature, 476, pp.163~169 (2011)
- Alimonti, A., "Subtle variations in Pten dose determine cancer susceptibility", Nat. Genet, 42, pp.454~458 (2010)
- Trotman, L. C., "Pten dose dictates cancer progression in the prostate", PLoS Biol, 1, pp.E59~ (2003)
- Garcia-Cao, I., "Systemic elevation of PTEN induces a tumor-suppressive metabolic state", Cell, 149, pp.49~62 (2012)
- Lee, Y. R., "Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway", Science, 364, pp.eaau0159~ (2019)
- Maccario, H., "PTEN is destabilized by phosphorylation on Thr366", Biochem. J, 405, pp.439~444 (2007)
- Vazquez, F., "Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex", J. Biol. Chem, 276, pp.48627~48630 (2001)
- Gonzalez-Santamaria, J., "Regulation of the tumor suppressor PTEN by SUMO", Cell Death Dis, 3, pp.e393~ (2012)
- Hershko, A., "The ubiquitin system", Annu. Rev. Biochem, 67, pp.425~479 (1998)
- Song, M. S., "The HECT family of E3 ubiquitin ligases and PTEN", Semin. Cancer Biol, 85, pp.43~51 (2021)
- Putz, U., "The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells", Sci. Signal, 5, pp.ra70~ (2012)
- Trotman, L. C., "Ubiquitination regulates PTEN nuclear import and tumor suppression", Cell, 128, pp.141~156 (2007)
- Maddika, S., "WWP2 is an E3 ubiquitin ligase for PTEN", Nat. Cell Biol, 13, pp.728~733 (2011)
- Wang, X., "NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN", Cell, 128, pp.129~139 (2007)
- Lee, Y. R., "WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition", N. Engl. J. Med, 382, pp.2103~2116 (2020)
- Nijman, S. M., "A genomic and functional inventory of deubiquitinating enzymes", Cell, 123, pp.773~786 (2005)
- Abdul Rehman, S. A., "MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes", Mol. Cell, 63, pp.146~155 (2016)
- Haahr, P., "ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability", Mol. Cell, 70, pp.165~174.e166 (2018)
- Kwasna, D., "Discovery and Characterization of ZUFSP", ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability, 2018, pp.70, 150~164.e156
- Clague, M. J., "Deubiquitylases from genes to organism", Physiol. Rev, 93, pp.1289~1315 (2013)
- Song, M. S., "The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network", Nature, 455, pp.813~817 (2008)
- Sacco, J. J., "The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells", Oncogene, 33, pp.4265~4272 (2014)
- Park, M. K., "PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression", Nat. Commun, 10, pp.636~ (2019)
- Yuan, L., "Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis", Nat. Cell Biol, 17, pp.1169~1181 (2015)
- Zhang, J., "Deubiquitylation and stabilization of PTEN by USP13", Nat. Cell Biol, 15, pp.1486~1494 (2013)
- Holowaty, M. N., "Protein interaction domains of the ubiquitin-specific protease, USP7", HAUSP, 2003, pp.278, 47753~47761
- Hu, M., "Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde", Cell, 111, pp.1041~1054 (2002)
- Sarkari, F., "USP7", HAUSP promotes the sequence-specific DNA binding activity of p53, 2010, pp.5, e13040~
- Li, M., "Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization", Nature, 416, pp.648~653 (2002)
- Cummins, J. M., "Tumour suppression: disruption of HAUSP gene stabilizes p53", Nature, 428, pp.1~ (2004)
- Kon, N., "Inactivation of HAUSP in vivo modulates p53 function", Oncogene, 29, pp.1270~1279 (2010)
- Faesen, A. C., "Mechanism of USP7", HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase, 2011, pp.44, 147~159
- An, L., "Dual-utility NLS drives RNF169-dependent DNA damage responses", Proc. Natl Acad. Sci, 114, pp.E2872~E2881 (2017)
- Cheng, J., "Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation", Nat. Commun, 6, pp.7023~ (2015)
- Zhang, Z. M., "An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1", Cell Rep, 12, pp.1400~1406 (2015)
- Howitt, J., "Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia", J. Cell Biol, 196, pp.29~36 (2012)
- Howitt, J., "Ndfip1 represses cell proliferation by controlling Pten localization and signaling specificity", J. Mol. Cell Biol, 7, pp.119~131 (2015)
- Carra, G., "Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia : a strategy to overcome TP53 mutated", deleted clones, 2017, pp.8, 35508~35522
- Gao, L., "Proteome Analysis of USP7 Substrates Revealed Its Role in Melanoma Through PI3K", Akt, Front. Oncol, pp.2021, 11[DOI]
- Hernandez-Perez, S., "DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin : molecular characterization and associations with breast cancer", Oncogene, 36, pp.4817~ (2017)
- Li, N., "USP7 inhibits TIMP2 by up-regulating the expression of EZH2 to activate the NF-kappaB", PD-L1 axis to promote the development of cervical cancer, 2022, pp.96, 110351~
- Wang, Z., "Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing", Acta Pharm. Sin. B, 11, pp.694~707 (2021)
- Zhao, G. Y., "USP7 overexpression predicts a poor prognosis in lung squamous cell carcinoma and large cell carcinoma", Tumour Biol, 36, pp.1721~1729 (2015)
- Collaud, S., "Lung neuroendocrine tumors : correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN", BMC Cancer, 15, pp.74~ (2015)
- Noguera, N. I., "Nucleophosmin", B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia, 2013, pp.27, 1037~1043
- Li, C., "TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies", J. Clin. Invest, 131, pp.e146893~ (2021)
- Morotti, A., "BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP", Leukemia, 28, pp.1326~1333 (2014)
- Yuan, J., "USP10 regulates p53 localization and stability by deubiquitinating p53", Cell, 140, pp.384~396 (2010)
- Deng, M., "Deubiquitination and Activation of AMPK by USP10", Mol. Cell, 61, pp.614~624 (2016)
- Liu, J., "Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13", Cell, 147, pp.223~234 (2011)
- Meyer, C., "The G3BP1-Family-USP10 Deubiquitinase Complex Rescues Ubiquitinated 40S Subunits of Ribosomes Stalled in Translation from Lysosomal Degradation", Mol. Cell, 77, pp.1193~1205.e1195 (2020)
- He, Y., "The deubiquitinase USP10 restores PTEN activity and inhibits nonsmall cell lung cancer cell proliferation", J. Biol. Chem, 297, pp.101088~ (2021)
- He, Y. M., "TRIM25 activates AKT", mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer, 2022, pp.43, 681~691
- Kim, K., "Prognostic significance of USP10 and p14ARF expression in patients with colorectal cancer", Pathol. Res. Pract, 216, pp.152988~ (2020)
- Song, J. S., "Dual loss of USP10 and p14ARF protein expression is associated with poor prognosis in patients with small intestinal adenocarcinoma", Tumour Biol, 40, pp.1010428318808678~ (2018)
- Swanson, D. A., "A ubiquitin C-terminal hydrolase gene on the proximal short arm of the X chromosome:implications for X-linked retinal disorders", Hum. Mol. Genet, 5, pp.533~538 (1996)
- Yang-Feng, T. L., "Frequent loss of heterozygosity on chromosomes Xp and 13q in human ovarian cancer", Int. J. Cancer, 52, pp.575~580 (1992)
- Spatz, A., "X-chromosome genetics and human cancer", Nat. Rev. Cancer, 4, pp.617~629 (2004)
- Medema, R. H., "The X factor: skewing X inactivation towards cancer", Cell, 129, pp.1253~1254 (2007)
- Liao, Y., "Ubiquitin specific peptidase 11as a novel therapeutic target for cancer management", Cell Death Disco, 8, pp.292~ (2022)
- Herold, S., "Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase", Nature, 567, pp.545~549 (2019)
- Wu, H. C., "USP11 regulates PML stability to control Notch-induced malignancy in brain tumours", Nat. Commun, 5, pp.3214~ (2014)
- Sun, W., "USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha", Cell Signal, 22, pp.386~394 (2010)
- Zhang, H., "Long noncoding RNA lnc-DILC stabilizes PTEN and suppresses clear cell renal cell carcinoma progression", Cell Biosci, 9, pp.81~ (2019)
- Kapadia, B., "Fatty Acid Synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL", Nat. Commun, 9, pp.829~ (2018)
- Wiltshire, T. D., "Sensitivity to poly(ADP-ribose)polymerase(PARP)inhibition identifies ubiquitin-specific peptidase 11(USP11)as a regulator of DNA doublestrand break repair", J. Biol. Chem, 285, pp.14565~14571 (2010)
- Gonzalez-Billalabeitia, E., "Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition", Cancer Disco, 4, pp.896~904 (2014)
- Fang, X., "Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination", J. Exp. Med, 214, pp.245~267 (2017)
- Han, C., "Amplification of USP13 drives ovarian cancer metabolism", Nat. Commun, 7, pp.13525~ (2016)
- Wu, Y., "Amplification of USP13 drives non-small cell lung cancer progression mediated by AKT", MAPK signaling, 2019, pp.114, 108831~
- Zhang, S., "Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors", Nat. Commun, 9, pp.215~ (2018)
- Morgan, E. L., "The deubiquitinase(DUB)USP13 promotes Mcl-1 stabilisation in cervical cancer", Oncogene, 40, pp.2112~2129 (2021)
- Zhou, Q., "Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism", J. Exp. Med, 217, pp.e20191779~ (2020)
- Li, Y., "USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response", Nat. Commun, 8, pp.15752~ (2017)
- Chu, Y., "The Chaperone BAG6 Regulates Cellular Homeostasis between Autophagy and Apoptosis by Holding LC3B", iScience, 23, pp.101708~ (2020)
- Kwon, J., "USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model", Oncogene, 41, pp.1974~1985 (2022)
- Man, X., "USP13 functions as a tumor suppressor by blocking the NF-kBmediated PTEN downregulation in human bladder cancer", J. Exp. Clin. Cancer Res, 38, pp.259~ (2019)
- Qu, Z., "USP13 serves as a tumor suppressor via the PTEN", AKT pathway in oral squamous cell carcinoma, 2019, pp.11, 9175~9183
- Zhang, Z., "Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity", Mol. Cell, 79, pp.304~319.e307 (2020)
- Zhou, N., "Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses", Cell Metab, 34, pp.1023~1041.e1028 (2022)
- Wang, M., "Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer", Nat. Commun, 12, pp.7006~ (2021)
- Du, T., "The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis", Nat. Commun, 10, pp.2914~ (2019)
- Costa Mdo, C., "Toward understanding Machado-Joseph disease", Prog. Neurobiol, 97, pp.239~257 (2012)
- Durcan, T. M., "Mutant ataxin-3 promotes the autophagic degradation of parkin", Autophagy, 7, pp.233~234 (2011)
- Scaglione, K. M., "Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP", Mol. Cell, 43, pp.599~612 (2011)
- Chakraborty, A., "Deficiency in classical nonhomologous end-joiningmediated repair of transcribed genes is linked to SCA3 pathogenesis", Proc. Natl Acad. Sci, 117, pp.8154~8165 (2020)
- Shi, Y., "PTEN is a protein tyrosine phosphatase for IRS1", Nat. Struct. Mol. Biol, 21, pp.522~527 (2014)
- Chauhan, D., "A small molecule inhibitor of ubiquitin-specific protease-7induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance", Cancer Cell, 22, pp.345~358 (2012)
- Turnbull, A. P., "Molecular basis of USP7 inhibition by selective smallmolecule inhibitors", Nature, 550, pp.481~486 (2017)
- Lamberto, I., "Structure-guided development of a potent and selective noncovalent active-site Inhibitor of USP7", Cell Chem. Biol, 24, pp.1490~1500 (2017)
- Kategaya, L., "USP7 small-molecule inhibitors interfere with ubiquitin binding", Nature, 550, pp.534~538 (2017)
- Hardie, D. G., "AMPK : a nutrient and energy sensor that maintains energy homeostasis", Nat. Rev. Mol. Cell Biol, 13, pp.251~262 (2012)
- Han, Y., "Ubiquitin-specific peptidase 7(USP7)and USP10 mediate deubiquitination of human NHE3 regulating its expression and activity", FASEB J, 34, pp.16476~16488 (2020)
- Maertens, G. N., "Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor", EMBO J, 29, pp.2553~2565 (2010)
- Okumura, K., "PCAF modulates PTEN activity", J. Biol. Chem, 281, pp.26562~26568 (2006)
- Zhang, J., "PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage", Cancer Disco, 9, pp.1306~1323 (2019)
- Ren, D., "USP22-mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression", Mol. Oncol, 16, pp.1200~1217 (2022)
- Shen, W. M., "Ubiquitin specific peptidase 49 inhibits non-small cell lung cancer cell growth by suppressing PI3K", AKT signaling, 2019, pp.35, 401~407
- Deng, R., "BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN", Mol. Oncol, 15, pp.279~298 (2021)
- Gavory, G., "Discovery and characterization of highly potent and selective allosteric USP7 inhibitors", Nat. Chem. Biol, 14, pp.118~125 (2018)
- Reverdy, C., "Discovery of specific inhibitors of human USP7", HAUSP deubiquitinating enzyme, 2012, pp.19, 467~477
- Burkhart, R. A., "Mitoxantrone targets human ubiquitin-specific peptidase 11(USP11)and is a potent inhibitor of pancreatic cancer cell survival", Mol. Cancer Res, 11, pp.901~911 (2013)
- "A small molecule inhibitor of deubiquitinase OTUD3 promotes DR5-induced apoptosis in lung cancer through ER stress modulation" (2021)[URL]
- Gertz, M., "Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism", Proc. Natl Acad. Sci, 110, pp.E2772~E2781 (2013)
- Wang, Q., "Inhibition of p97-dependent protein degradation by Eeyarestatin I", J. Biol. Chem, 283, pp.7445~7454 (2008)
