UFMylation System: An Emerging Player in Tumorigenesis
Abstract
:Simple Summary
Abstract
1. Introduction
2. The UFM1 (De-)Conjugation System
2.1. UBA5
2.2. UFC1
2.3. UFL1
2.4. UFSP1 and UFSP2
3. The Physiological Function of UFMylation
3.1. ER Stress
3.2. DNA Damage Response
3.3. Erythroid Development
4. Aberrant UFMylation Contributes to Various Tumors
4.1. Breast Cancer
4.2. Gastric Cancer
4.3. Colon Cancer
4.4. Hepatocellular Carcinoma
4.5. Lung Cancer
4.6. Others
5. Future Perspectives
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AKR1C | Aldo-keto reductase 1C |
ASC1 | Activating signal co-integrator 1 |
ATF6 | Activating transcription factor 6 |
ATM | Ataxia–telangiectasia mutated |
CDK5 | Cyclin-dependent kinase 5 |
DDR | DNA damage response |
DSBs | Double-strand breaks |
DUBs | Deubiquitinating enzymes |
ER | Endoplasmic reticulum |
ERα | Estrogen receptor-α |
ERAD | ER-associated degradation |
HCC | Hepatocellular carcinoma |
HR | Homologous recombination |
HSC | Hematopoietic stem cell |
IRE1α | Inositol-requiring enzyme 1α |
lincRNA | Long intergenic RNA |
LncRNA | Long non-coding RNA |
NHEJ | Non-homologous end-joining |
NLS | Nuclear localization signal |
PERK | Protein kinase-like ER kinase |
PTMs | Post-translational modifications |
RING | Really interesting new gene |
SCNAs | Somatic copy number alterations |
UBA5 | Ubiquitin-like modifier-activating enzyme 5 |
UBLs | Ubiquitin-like molecules |
UFC1 | UFM1-conjugating enzyme 1 |
UFL1 | UFM1-specific ligase 1 |
UFM1 | Ubiquitin-fold modifier 1 |
ULPs | Ubiquitin-like protein-specific proteases |
UPR | Unfolded protein response |
References
- Herhaus, L.; Dikic, I. Expanding the ubiquitin code through post-translational modification. EMBO Rep. 2015, 16, 1071–1083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Komatsu, M.; Chiba, T.; Tatsumi, K.; Iemura, S.; Tanida, I.; Okazaki, N.; Ueno, T.; Kominami, E.; Natsume, T.; Tanaka, K. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. Embo J. 2004, 23, 1977–1986. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sasakawa, H.; Sakata, E.; Yamaguchi, Y.; Komatsu, M.; Tatsumi, K.; Kominami, E.; Tanaka, K.; Kato, K. Solution structure and dynamics of Ufm1, a ubiquitin-fold modifier 1. Biochem. Biophys. Res. Commun. 2006, 343, 21–26. [Google Scholar] [CrossRef] [PubMed]
- Cappadocia, L.; Lima, C.D. Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism. Chem. Rev. 2018, 118, 889–918. [Google Scholar] [CrossRef]
- Gerakis, Y.; Quintero, M.; Li, H.; Hetz, C. The UFMylation System in Proteostasis and Beyond. Trends Cell Biol. 2019, 29, 974–986. [Google Scholar] [CrossRef] [PubMed]
- Lu, H.; Yang, Y.; Allister, E.M.; Wijesekara, N.; Wheeler, M.B. The identification of potential factors associated with the development of type 2 diabetes: A quantitative proteomics approach. Mol. Cell. Proteom. 2008, 7, 1434–1451. [Google Scholar] [CrossRef] [Green Version]
- Lemaire, K.; Moura, R.F.; Granvik, M.; Igoillo-Esteve, M.; Hohmeier, H.E.; Hendrickx, N.; Newgard, C.B.; Waelkens, E.; Cnop, M.; Schuit, F. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS ONE 2011, 6, e18517. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Yue, G.; Ma, W.; Zhang, A.; Zou, J.; Cai, Y.; Tang, X.; Wang, J.; Liu, J.; Li, H.; et al. Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure. Circ. Heart Fail. 2018, 11, e4917. [Google Scholar] [CrossRef]
- Azfer, A.; Niu, J.; Rogers, L.M.; Adamski, F.M.; Kolattukudy, P.E. Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H1411–H1420. [Google Scholar] [CrossRef] [Green Version]
- Cai, Y.; Zhu, G.; Liu, S.; Pan, Z.; Quintero, M.; Poole, C.J.; Lu, C.; Zhu, H.; Islam, B.; Riggelen, J.V.; et al. Indispensable role of the Ubiquitin-fold modifier 1-specific E3 ligase in maintaining intestinal homeostasis and controlling gut inflammation. Cell Discov. 2019, 5, 7. [Google Scholar] [CrossRef]
- Yang, R.; Wang, H.; Kang, B.; Chen, B.; Shi, Y.; Yang, S.; Sun, L.; Liu, Y.; Xiao, W.; Zhang, T.; et al. CDK5RAP3, a UFL1 sub-strate adaptor, is crucial for liver development. Development 2019, 146, dev169235. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Watson, C.M.; Crinnion, L.A.; Gleghorn, L.; Newman, W.G.; Ramesar, R.; Beighton, P.; Wallis, G.A. Identification of a mu-tation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia. S. Afr. Med. J. 2015, 105, 558–563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wei, Y.; Xu, X. UFMylation: A Unique & Fashionable Modification for Life. Genom. Proteom. Bioinform. 2016, 14, 140–146. [Google Scholar] [CrossRef] [Green Version]
- Mignon-Ravix, C.; Milh, M.; Kaiser, C.S.; Daniel, J.; Riccardi, F.; Cacciagli, P.; Nagara, M.; Busa, T.; Liebau, E.; Villard, L. Abnormal function of the UBA5 protein in a case of early developmental and epileptic encephalopathy with suppres-sion-burst. Hum. Mutat. 2018, 39, 934–938. [Google Scholar] [CrossRef] [PubMed]
- Nahorski, M.S.; Maddirevula, S.; Ishimura, R.; Alsahli, S.; Brady, A.F.; Begemann, A.; Mizushima, T.; Guzmán-Vega, F.J.; Obata, M.; Ichimura, Y.; et al. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain devel-opment. Brain 2018, 141, 1934–1945. [Google Scholar] [CrossRef] [Green Version]
- Hamilton, E.; Bertini, E.; Kalaydjieva, L.; Morar, B.; Dojčáková, D.; Liu, J.; Vanderver, A.; Curiel, J.; Persoon, C.M.; Diodato, D.; et al. UFM1 founder mutation in the Roma population causes recessive variant of H-ABC. Neurology 2017, 89, 1821–1828. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kang, S.H.; Kim, G.R.; Seong, M.; Baek, S.H.; Seol, J.H.; Bang, O.S.; Ovaa, H.; Tatsumi, K.; Komatsu, M.; Tanaka, K.; et al. Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2. J. Biol. Chem. 2007, 282, 5256–5262. [Google Scholar] [CrossRef] [Green Version]
- Ha, B.H.; Ahn, H.C.; Kang, S.H.; Tanaka, K.; Chung, C.H.; Kim, E.E. Structural basis for Ufm1 processing by UfSP1. J. Biol. Chem. 2008, 283, 14893–14900. [Google Scholar] [CrossRef] [Green Version]
- Ha, B.H.; Jeon, Y.J.; Shin, S.C.; Tatsumi, K.; Komatsu, M.; Tanaka, K.; Watson, C.M.; Wallis, G.; Chung, C.H.; Kim, E.E. Structure of ubiquitin-fold modifier 1-specific protease UfSP2. J. Biol. Chem. 2011, 286, 10248–10257. [Google Scholar] [CrossRef] [Green Version]
- Schulman, B.A.; Harper, J.W. Ubiquitin-like protein activation by E1 enzymes: The apex for downstream signalling path-ways. Nat. Rev. Mol. Cell Biol. 2009, 10, 319–331. [Google Scholar] [CrossRef] [Green Version]
- Bacik, J.P.; Walker, J.R.; Ali, M.; Schimmer, A.D.; Dhe-Paganon, S. Crystal structure of the human ubiquitin-activating en-zyme 5 (UBA5) bound to ATP: Mechanistic insights into a minimalistic E1 enzyme. J. Biol. Chem. 2010, 285, 20273–20280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Soudah, N.; Padala, P.; Hassouna, F.; Kumar, M.; Mashahreh, B.; Lebedev, A.A.; Isupov, M.N.; Cohen-Kfir, E.; Wiener, R. An N-Terminal Extension to UBA5 Adenylation Domain Boosts UFM1 Activation: Isoform-Specific Differences in Ubiqui-tin-like Protein Activation. J. Mol. Biol. 2019, 431, 463–478. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gavin, J.M.; Hoar, K.; Xu, Q.; Ma, J.; Lin, Y.; Chen, J.; Chen, W.; Bruzzese, F.J.; Harrison, S.; Mallender, W.D.; et al. Mecha-nistic study of Uba5 enzyme and the Ufm1 conjugation pathway. J. Biol. Chem. 2014, 289, 22648–22658. [Google Scholar] [CrossRef] [Green Version]
- Zheng, M.; Gu, X.; Zheng, D.; Yang, Z.; Li, F.; Zhao, J.; Xie, Y.; Ji, C.; Mao, Y. UBE1DC1, an ubiquitin-activating enzyme, activates two different ubiquitin-like proteins. J. Cell. Biochem. 2008, 104, 2324–2334. [Google Scholar] [CrossRef] [PubMed]
- Tatsumi, K.; Yamamoto-Mukai, H.; Shimizu, R.; Waguri, S.; Sou, Y.S.; Sakamoto, A.; Taya, C.; Shitara, H.; Hara, T.; Chung, C.H.; et al. The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. Nat. Commun. 2011, 2, 181. [Google Scholar] [CrossRef] [PubMed]
- Colin, E.; Daniel, J.; Ziegler, A.; Wakim, J.; Scrivo, A.; Haack, T.B.; Khiati, S.; Denommé, A.S.; Amati-Bonneau, P.; Charif, M.; et al. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy. Am. J. Hum. Genet. 2016, 99, 695–703. [Google Scholar] [CrossRef] [Green Version]
- Muona, M.; Ishimura, R.; Laari, A.; Ichimura, Y.; Linnankivi, T.; Keski-Filppula, R.; Herva, R.; Rantala, H.; Paetau, A.; Pöyhönen, M.; et al. Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe In-fantile-Onset Encephalopathy. Am. J. Hum. Genet. 2016, 99, 683–694. [Google Scholar] [CrossRef] [Green Version]
- Duan, R.; Shi, Y.; Yu, L.; Zhang, G.; Li, J.; Lin, Y.; Guo, J.; Wang, J.; Shen, L.; Jiang, H.; et al. UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia. PLoS ONE 2016, 11, e149039. [Google Scholar] [CrossRef]
- Arnadottir, G.A.; Jensson, B.O.; Marelsson, S.E.; Sulem, G.; Oddsson, A.; Kristjansson, R.P.; Benonisdottir, S.; Gudjonsson, S.A.; Masson, G.; Thorisson, G.A.; et al. Compound heterozygous mutations in UBA5 causing early-onset epileptic enceph-alopathy in two sisters. BMC Med. Genet. 2017, 18, 103. [Google Scholar] [CrossRef] [Green Version]
- Cabrera-Serrano, M.; Coote, D.J.; Azmanov, D.; Goullee, H.; Andersen, E.; Mclean, C.; Davis, M.; Ishimura, R.; Stark, Z.; Vallat, J.M.; et al. A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy. J. Med. Genet. 2020, 57, 835–842. [Google Scholar] [CrossRef]
- Liu, G.; Forouhar, F.; Eletsky, A.; Atreya, H.S.; Aramini, J.M.; Xiao, R.; Huang, Y.J.; Abashidze, M.; Seetharaman, J.; Liu, J.; et al. NMR and X-RAY structures of human E2-like ubiquitin-fold modifier conjugating enzyme 1 (UFC1) reveal structural and functional conservation in the metazoan UFM1-UBA5-UFC1 ubiquination pathway. J. Struct. Funct. Genom. 2009, 10, 127–136. [Google Scholar] [CrossRef]
- Liu, G.; Aramini, J.; Atreya, H.S.; Eletsky, A.; Xiao, R.; Acton, T.; Ma, L.; Montelione, G.T.; Szyperski, T. GFT NMR based resonance assignment for the 21 kDa human protein UFC1. J. Biomol. NMR 2005, 32, 261. [Google Scholar] [CrossRef] [PubMed]
- Xie, S. Characterization, crystallization and preliminary X-ray crystallographic analysis of the human Uba5 C-terminus-Ufc1 complex. Acta Crystallogr. Sect. F Struct. Biol. Commun. 2014, 70, 1093–1097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Homrich, M.; Wobst, H.; Laurini, C.; Sabrowski, J.; Schmitz, B.; Diestel, S. Cytoplasmic domain of NCAM140 interacts with ubiquitin-fold modifier-conjugating enzyme-1 (Ufc1). Exp. Cell Res. 2014, 324, 192–199. [Google Scholar] [CrossRef] [PubMed]
- Yu, T.; Shan, T.D.; Li, J.Y.; Huang, C.Z.; Wang, S.Y.; Ouyang, H.; Lu, X.J.; Xu, J.H.; Zhong, W.; Chen, Q.K. Knockdown of linc-UFC1 suppresses proliferation and induces apoptosis of colorectal cancer. Cell Death Dis. 2016, 7, e2228. [Google Scholar] [CrossRef]
- Liu, P.; Sun, Q.Q.; Liu, T.X.; Lu, K.; Zhang, N.; Zhu, Y.; Chen, M. Serum lncRNA-UFC1 as a potential biomarker for diagno-sis and prognosis of pancreatic cancer. Int. J. Clin. Exp. Pathol. 2019, 12, 4125–4129. [Google Scholar]
- Xie, R.; Wang, M.; Zhou, W.; Wang, D.; Yuan, Y.; Shi, H.; Wu, L. Long Non-Coding RNA (LncRNA) UFC1/miR-34a Con-tributes to Proliferation and Migration in Breast Cancer. Med. Sci. Monit. 2019, 25, 7149–7157. [Google Scholar] [CrossRef]
- Zhang, X.; Liang, W.; Liu, J.; Zang, X.; Gu, J.; Pan, L.; Shi, H.; Fu, M.; Huang, Z.; Zhang, Y.; et al. Long non-coding RNA UFC1 promotes gastric cancer progression by regulating miR-498/Lin28b. J. Exp. Clin. Cancer Res. 2018, 37, 134. [Google Scholar] [CrossRef] [Green Version]
- Shiwaku, H.; Yoshimura, N.; Tamura, T.; Sone, M.; Ogishima, S.; Watase, K.; Tagawa, K.; Okazawa, H. Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity. Embo J. 2010, 29, 2446–2460. [Google Scholar] [CrossRef] [Green Version]
- Tatsumi, K.; Sou, Y.S.; Tada, N.; Nakamura, E.; Iemura, S.; Natsume, T.; Kang, S.H.; Chung, C.H.; Kasahara, M.; Kominami, E.; et al. A novel type of E3 ligase for the Ufm1 conjugation system. J. Biol. Chem. 2010, 285, 5417–5427. [Google Scholar] [CrossRef] [Green Version]
- Yoo, H.M.; Kang, S.H.; Kim, J.Y.; Lee, J.E.; Seong, M.W.; Lee, S.W.; Ka, S.H.; Sou, Y.S.; Komatsu, M.; Tanaka, K.; et al. Modi-fication of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development. Mol. Cell 2014, 56, 261–274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, J.; Lei, G.; Mei, M.; Tang, Y.; Li, H. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling. J. Biol. Chem. 2010, 285, 15126–15136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kwon, J.; Cho, H.J.; Han, S.H.; No, J.G.; Kwon, J.Y.; Kim, H. A novel LZAP-binding protein, NLBP, inhibits cell invasion. J. Biol. Chem. 2010, 285, 12232–12240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, M.; Zhu, X.; Zhang, Y.; Cai, Y.; Chen, J.; Sivaprakasam, S.; Gurav, A.; Pi, W.; Makala, L.; Wu, J.; et al. RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death Differ. 2015, 22, 1922–1934. [Google Scholar] [CrossRef]
- Miller, C.; Cai, Y.; Patton, T.; Graves, S.H.; Li, H.; Sabbatini, M.E. RCAD/BiP pathway is necessary for the proper synthesis of digestive enzymes and secretory function of the exocrine pancreas. Am. J. Physiol.-Gastrointest. Liver Physiol. 2017, 312, G314–G326. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Ye, X.; Zhang, C.; Wang, J.; Guan, Z.; Yan, J.; Xu, L.; Wang, K.; Guan, D.; Liang, Q.; et al. Ufl1 deficiency causes kidney atrophy associated with disruption of endoplasmic reticulum homeostasis. J. Genet. Genom. 2021, 48, 403–410. [Google Scholar] [CrossRef]
- Kim, T.; Croce, C.M. MicroRNA and ER stress in cancer. Semin. Cancer Biol. 2021, 75, 3–14. [Google Scholar] [CrossRef]
- Hetz, C. The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell. Biol. 2012, 13, 89–102. [Google Scholar] [CrossRef]
- Guerriero, C.J.; Brodsky, J.L. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol. Rev. 2012, 92, 537–576. [Google Scholar] [CrossRef]
- Hwang, J.; Qi, L. Quality Control in the Endoplasmic Reticulum: Crosstalk between ERAD and UPR pathways. Trends Biochem. Sci. 2018, 43, 593–605. [Google Scholar] [CrossRef]
- Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007, 8, 519–529. [Google Scholar] [CrossRef] [PubMed]
- Sun, Z.; Brodsky, J.L. Protein quality control in the secretory pathway. J. Cell Biol. 2019, 218, 3171–3187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Y.; Zhang, M.; Wu, J.; Lei, G.; Li, H. Transcriptional regulation of the Ufm1 conjugation system in response to dis-turbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS ONE 2012, 7, e48587. [Google Scholar] [CrossRef] [Green Version]
- Hu, X.; Pang, Q.; Shen, Q.; Liu, H.; He, J.; Wang, J.; Xiong, J.; Zhang, H.; Chen, F. Ubiquitin-fold modifier 1 inhibits apopto-sis by suppressing the endoplasmic reticulum stress response in Raw264.7 cells. Int. J. Mol. Med. 2014, 33, 1539–1546. [Google Scholar] [CrossRef] [Green Version]
- Liu, J.; Wang, Y.; Song, L.; Zeng, L.; Yi, W.; Liu, T.; Chen, H.; Wang, M.; Ju, Z.; Cong, Y.S. A critical role of DDRGK1 in en-doplasmic reticulum homoeostasis via regulation of IRE1α stability. Nat. Commun. 2017, 8, 14186. [Google Scholar] [CrossRef]
- Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature 2009, 461, 1071–1078. [Google Scholar] [CrossRef] [Green Version]
- Shiloh, Y.; Ziv, Y. The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 2013, 14, 197–210. [Google Scholar] [CrossRef]
- Paull, T.T. Mechanisms of ATM Activation. Annu. Rev. Biochem. 2015, 84, 711–738. [Google Scholar] [CrossRef]
- Wang, Z.; Gong, Y.; Peng, B.; Shi, R.; Fan, D.; Zhao, H.; Zhu, M.; Zhang, H.; Lou, Z.; Zhou, J.; et al. MRE11 UFMylation promotes ATM activation. Nucleic Acids Res. 2019, 47, 4124–4135. [Google Scholar] [CrossRef] [Green Version]
- Lee, L.; Perez, O.A.; Martinez-Balsalobre, E.; Churikov, D.; Peter, J.; Rahmouni, D.; Audoly, G.; Azzoni, V.; Audebert, S.; Camoin, L.; et al. UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival. Sci. Adv. 2021, 7, c7371. [Google Scholar] [CrossRef]
- Qin, B.; Yu, J.; Nowsheen, S.; Wang, M.; Tu, X.; Liu, T.; Li, H.; Wang, L.; Lou, Z. UFL1 promotes histone H4 ufmylation and ATM activation. Nat. Commun. 2019, 10, 1242. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Guan, D.; Dong, M.; Yang, J.; Wei, H.; Liang, Q.; Song, L.; Xu, L.; Bai, J.; Liu, C.; et al. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nat. Cell Biol. 2020, 22, 1056–1063. [Google Scholar] [CrossRef]
- Cai, Y.; Pi, W.; Sivaprakasam, S.; Zhu, X.; Zhang, M.; Chen, J.; Makala, L.; Lu, C.; Wu, J.; Teng, Y.; et al. UFBP1, a Key Com-ponent of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development. PLoS Genet. 2015, 11, e1005643. [Google Scholar] [CrossRef] [PubMed]
- Liu, D.; Wang, W.D.; Melville, D.B.; Cha, Y.I.; Yin, Z.; Issaeva, N.; Knapik, E.W.; Yarbrough, W.G. Tumor suppressor Lzap regulates cell cycle progression, doming, and zebrafish epiboly. Dev. Dyn. 2011, 240, 1613–1625. [Google Scholar] [CrossRef] [Green Version]
- Harbeck, N.; Gnant, M. Breast cancer. Lancet 2017, 389, 1134–1150. [Google Scholar] [CrossRef]
- Hart, C.D.; Migliaccio, I.; Malorni, L.; Guarducci, C.; Biganzoli, L.; Di Leo, A. Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat. Rev. Clin. Oncol. 2015, 12, 541–552. [Google Scholar] [CrossRef]
- Yang, J.; Zhou, Y.; Xie, S.; Wang, J.; Li, Z.; Chen, L.; Mao, M.; Chen, C.; Huang, A.; Chen, Y.; et al. Metformin induces Fer-roptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J. Exp. Clin. Cancer Res. 2021, 40, 206. [Google Scholar] [CrossRef]
- Fang, B.; Li, Z.; Qiu, Y.; Cho, N.; Yoo, H.M. Inhibition of UBA5 Expression and Induction of Autophagy in Breast Cancer Cells by Usenamine A. Biomolecules 2021, 11, 1348. [Google Scholar] [CrossRef]
- Lin, J.X.; Xie, X.S.; Weng, X.F.; Qiu, S.L.; Yoon, C.; Lian, N.Z.; Xie, J.W.; Wang, J.B.; Lu, J.; Chen, Q.Y.; et al. UFM1 suppresses invasive activities of gastric cancer cells by attenuating the expression of PDK1 through PI3K/AKT signaling. J. Exp. Clin. Cancer Res. 2019, 38, 410. [Google Scholar] [CrossRef]
- Lin, J.X.; Xie, X.S.; Weng, X.F.; Zheng, C.H.; Xie, J.W.; Wang, J.B.; Lu, J.; Chen, Q.Y.; Cao, L.L.; Lin, M.; et al. Low expression of CDK5RAP3 and DDRGK1 indicates a poor prognosis in patients with gastric cancer. World J. Gastroenterol. 2018, 24, 3898–3907. [Google Scholar] [CrossRef]
- Hu, Z.; Wang, X.; Li, D.; Cao, L.; Cui, H.; Xu, G. UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2. Oncogene 2021, 40, 647–662. [Google Scholar] [CrossRef] [PubMed]
- Zheng, C.H.; Wang, J.B.; Lin, M.Q.; Zhang, P.Y.; Liu, L.C.; Lin, J.X.; Lu, J.; Chen, Q.Y.; Cao, L.L.; Lin, M.; et al. CDK5RAP3 suppresses Wnt/β-catenin signaling by inhibiting AKT phosphorylation in gastric cancer. J. Exp. Clin. Cancer Res. 2018, 37, 59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, J.B.; Wang, Z.W.; Li, Y.; Huang, C.Q.; Zheng, C.H.; Li, P.; Xie, J.W.; Lin, J.X.; Lu, J.; Chen, Q.Y.; et al. CDK5RAP3 acts as a tumor suppressor in gastric cancer through inhibition of β-catenin signaling. Cancer Lett. 2017, 385, 188–197. [Google Scholar] [CrossRef] [PubMed]
- Zhou, J.; Ma, X.; Xu, L.; Liang, Q.; Mao, J.; Liu, J.; Wang, M.; Yuan, J.; Cong, Y.S. Genomic profiling of the UFMylation fam-ily genes identifies UFSP2 as a potential tumour suppressor in colon cancer. Clin. Transl. Med. 2021, 11, e642. [Google Scholar] [CrossRef]
- Walczak, C.P.; Leto, D.E.; Zhang, L.; Riepe, C.; Muller, R.Y.; Darosa, P.A.; Ingolia, N.T.; Elias, J.E.; Kopito, R.R. Ribosomal protein RPL26 is the principal target of UFMylation. Proc. Natl. Acad. Sci. USA 2019, 116, 1299–1308. [Google Scholar] [CrossRef] [Green Version]
- Yang, J.D.; Hainaut, P.; Gores, G.J.; Amadou, A.; Plymoth, A.; Roberts, L.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 589–604. [Google Scholar] [CrossRef]
- Chen, E.; Zhou, B.; Bian, S.; Ni, W.; Chen, Z. The lncRNA B3GALT5-AS1 Functions as an HCC Suppressor by Regulating the miR-934/UFM1 Axis. J. Oncol. 2021, 2021, 1776432. [Google Scholar] [CrossRef]
- Mak, G.W.; Chan, M.M.; Leong, V.Y.; Lee, J.M.; Yau, T.O.; Ng, I.O.; Ching, Y.P. Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Res. 2011, 71, 2949–2958. [Google Scholar] [CrossRef] [Green Version]
- Mak, G.W.; Lai, W.L.; Zhou, Y.; Li, M.; Ng, I.O.; Ching, Y.P. CDK5RAP3 is a novel repressor of p14ARF in hepatocellular carcinoma cells. PLoS ONE 2012, 7, e42210. [Google Scholar] [CrossRef] [Green Version]
- Zhao, J.J.; Pan, K.; Li, J.J.; Chen, Y.B.; Chen, J.G.; Lv, L.; Wang, D.D.; Pan, Q.Z.; Chen, M.S.; Xia, J.C. Identification of LZAP as a new candidate tumor suppressor in hepatocellular carcinoma. PLoS ONE 2011, 6, e26608. [Google Scholar] [CrossRef]
- Kim, C.H.; Nam, H.S.; Lee, E.H.; Han, S.H.; Cho, H.J.; Chung, H.J.; Lee, N.S.; Choi, S.J.; Kim, H.; Ryu, J.S.; et al. Overexpres-sion of a novel regulator of p120 catenin, NLBP, promotes lung adenocarcinoma proliferation. Cell Cycle 2013, 12, 2443–2453. [Google Scholar] [CrossRef] [Green Version]
- Da, S.S.; Paiva, S.L.; Bancerz, M.; Geletu, M.; Lewis, A.M.; Chen, J.; Cai, Y.; Lukkarila, J.L.; Li, H.; Gunning, P.T. A selective inhibitor of the UFM1-activating enzyme, UBA5. Bioorg. Med. Chem. Lett. 2016, 26, 4542–4547. [Google Scholar] [CrossRef]
- Stav, D.; Bar, I.; Sandbank, J. Usefulness of CDK5RAP3, CCNB2, and RAGE genes for the diagnosis of lung adenocarcinoma. Int. J. Biol. Markers 2007, 22, 108–113. [Google Scholar] [CrossRef] [PubMed]
- Roberts, A.M.; Miyamoto, D.K.; Huffman, T.R.; Bateman, L.A.; Ives, A.N.; Akopian, D.; Heslin, M.J.; Contreras, C.M.; Rape, M.; Skibola, C.F.; et al. Chemoproteomic Screening of Covalent Ligands Reveals UBA5 As a Novel Pancreatic Cancer Tar-get. ACS Chem. Biol. 2017, 12, 899–904. [Google Scholar] [CrossRef]
- Xi, P.; Ding, D.; Zhou, J.; Wang, M.; Cong, Y.S. DDRGK1 regulates NF-κB activity by modulating IκBα stability. PLoS ONE 2013, 8, e64231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.; Li, C.; Wang, Y.; Li, L.; Han, Z.; Wang, G. UFL1 Alleviates LPS-Induced Apoptosis by Regulating the NF-κB Signaling Pathway in Bovine Ovarian Granulosa Cells. Biomolecules 2020, 10, 260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liang, J.R.; Lingeman, E.; Luong, T.; Ahmed, S.; Muhar, M.; Nguyen, T.; Olzmann, J.A.; Corn, J.E. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. Cell 2020, 180, 1160–1177. [Google Scholar] [CrossRef]
Cancer | Gene Analyzed | Phenotype | Possible Mechanism | Ref. |
---|---|---|---|---|
Breast cancer | ASC1 | UFMylation of ASC1 promoted the breast cancer cell growth and tumor formation | The polyufmylated ASC1 enhanced the association of p300, SRC1, and itself to the promoters of ERα target genes | [41] |
SLC7A11 | Metformin suppressed tumor growth via reducing its stability | Metformin exerted anti-cancer effect in breast cancer by inhibiting the UFMylation of SLC7A11 | [67] | |
UBA5 | Upregulated in breast cancer | Inhibitor-induced apoptosis, autophagy and ER stress in breast cancer cells | [68] | |
LncUFC1 | Upregulated in breast tissues and cell lines | Promoting the proliferation and migration of breast cancers via miR-34a/CXCL10 axis | [37] | |
Gastric cancer | UFM1 | Upregulated in gastric tissues and cell lines | Suppressing gastric cancer development by attenuating the expression of PDK1 | [69] |
UFBP1 | High expression enhanced drug sensitivity in gastric cancer patients | Enhancing the sensitivity of gastric cancer cells to chemotherapy through the Nrf2/AKR1C axis | [71] | |
CDK5RAP3 | Low expression indicated a worse outcome of gastric cancer patients | Suppressing the development of gastric cancer via inhibiting Akt/GSK-3β and Wnt/β-catenin signaling | [72,73] | |
LncUFC1 | Downregulated in gastric tissues | Promoting gastric cancer development by regulating miR-498/Lin28b pathway | [38] | |
Colon cancer | UFSP2 | Decreased in colon cancer patients | Suppressing the growth rates of colon cancer cells and xenograft tumors | [74] |
LincUFC1 | Overexpressed in colorectal tissues | Promoting the colorectal cancer growth by regulating the β-catenin and p38 signaling | [35] | |
Hepatocellular carcinoma | UFM1 | Decreased in hepatocellular carcinoma tissues | Direct mechanism unknown | [77] |
UFL1 | Detected in hepatocellular carcinoma cell line | Preventing cell invasion, inhibiting NF-kB signaling | [43] | |
CDK5RAP3 | Controversial | Controversial | [78,79,80] | |
Lung cancer | UFL1 | Upregulated in lung adenocarcinoma tissues | Inhibiting the ubiquitin-mediated proteasome degradation of p120 catenin | [81] |
UBA5 | Design an UBA5 inhibitor | Inhibitor reduced the proliferation of lung cancer cells | [82] | |
CDK5RAP3 | Elevated in lung adenocarcinoma tissues | Unknown | [83] | |
Pancreatic cancer | UBA5 | Chemoproteomic screening identified | Knockdown impaired pancreatic cancer pathogenicity | [84] |
Osteosarcoma | UFBP1 | Depletion inhibited cell proliferation and invasion | Suppressing the NF-kB transcriptional activity | [85] |
Ovarian granulosa cells | UFL1 | Alleviating the LPS-induced apoptosis in ovarian granulosa cells | Regulating the NF-κB pathway | [86] |
Substrate | Modification Sites | Function after UFMylation Modification | Ref. |
---|---|---|---|
UFBP1 | Lys267 | Maintaining ER homeostasis | [40] |
ASC1 | Lys324, Lys325, Lys334 and Lys367 | Transactivation of ERα and promoting breast cancer development | [41] |
p53 | Lys351, Lys357, Lys370 and Lys373 | Maintaining p53 stability and suppressing tumor progression | [62] |
RPL26 | Lys132 and Lys134 | Protein biogenesis at the ER. | [75] |
RPN1 | Unknown | ER phagy | [87] |
MRE11 | Lys282 | Promoting ATM activation, DSB repair and genome stability | [59] |
Histone H4 | Lys31 | Promoting ATM activation and maintaining genomic integrity | [61] |
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Jing, Y.; Mao, Z.; Chen, F. UFMylation System: An Emerging Player in Tumorigenesis. Cancers 2022, 14, 3501. https://doi.org/10.3390/cancers14143501
Jing Y, Mao Z, Chen F. UFMylation System: An Emerging Player in Tumorigenesis. Cancers. 2022; 14(14):3501. https://doi.org/10.3390/cancers14143501
Chicago/Turabian StyleJing, Yu, Ziming Mao, and Fengling Chen. 2022. "UFMylation System: An Emerging Player in Tumorigenesis" Cancers 14, no. 14: 3501. https://doi.org/10.3390/cancers14143501