Abstract
Background: cGAS-STING signaling has been primarily discovered as an important DNA sensing machinery, bridging innate immunity and adaptive immunity. Beyond its antiviral response, recent evidence expanded its complicated role in cancer therapy.
Methods: UALCAN, The TCGA Wander, GEPIA, SMART, TIMER, Kaplan-Meier plotter, TCGA Data, and cBioPortal were utilized in the investigation.
Results: We evaluated the expression of four key molecules (MB21D1, TMEM173, TBK1, and IRF3) in the cGAS-STING pathway and found that the TMEM173 gene was significantly downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Not only immunostimulatory cells but also regulatory T cells were triggered by the DNA sensing pathway. With gene enrichment analysis, we revealed that cell cycle and mechanotransduction/cytoskeleton signals were most closely connected with cGAS-STING signal alterations in non-small-cell lung cancer (NSCLC). cGAS-STING signaling was robustly correlated with methylation changes, especially histone H3K4 lysine demethylase KDM5s. Transient activation of cGAS-STING was found to exert tumor surveillance effect, and inhibition of STING signaling co-opt elevated KDM5 demethylases might inadvertently worsen clinical outcomes.
Conclusion: cGAS-STING signaling and KDM5 demethylases have the potential to be used as targets for evaluating an effective immune response in the tumor microenvironment.
Keywords: cGAS/STING, KDM5 histone demethylases, methylation, immune infiltrating cells, prognosis, lung cancer.
[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Travis, W.D.; Brambilla, E.; Burke, A.P.; Marx, A.; Nichol-son, A.G. Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J. Thorac. Oncol., 2015, 10(9), 1240-1242.
[http://dx.doi.org/10.1097/JTO.0000000000000663] [PMID: 26291007]
[http://dx.doi.org/10.1097/JTO.0000000000000663] [PMID: 26291007]
[3]
Sharma, P.; Hu-Lieskovan, S.; Wargo, J.A.; Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell, 2017, 168(4), 707-723.
[http://dx.doi.org/10.1016/j.cell.2017.01.017] [PMID: 28187290]
[http://dx.doi.org/10.1016/j.cell.2017.01.017] [PMID: 28187290]
[4]
O’Donnell, J.S.; Teng, M.W.L.; Smyth, M.J. Cancer immuno-editing and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol., 2019, 16(3), 151-167.
[http://dx.doi.org/10.1038/s41571-018-0142-8] [PMID: 30523282]
[http://dx.doi.org/10.1038/s41571-018-0142-8] [PMID: 30523282]
[5]
Lu, S.; Concha-Benavente, F.; Shayan, G.; Srivastava, R.M.; Gibson, S.P.; Wang, L.; Gooding, W.E.; Ferris, R.L. STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer. Oral Oncol., 2018, 78, 186-193.
[http://dx.doi.org/10.1016/j.oraloncology.2018.01.019] [PMID: 29496049]
[http://dx.doi.org/10.1016/j.oraloncology.2018.01.019] [PMID: 29496049]
[6]
Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science, 2013, 339(6121), 786-791.
[http://dx.doi.org/10.1126/science.1232458] [PMID: 23258413]
[http://dx.doi.org/10.1126/science.1232458] [PMID: 23258413]
[7]
Zhang, X.; Bai, X.C.; Chen, Z.J. Structures and mechanisms in the cGAS-STING innate immunity pathway. Immunity, 2020, 53(1), 43-53.
[http://dx.doi.org/10.1016/j.immuni.2020.05.013] [PMID: 32668227]
[http://dx.doi.org/10.1016/j.immuni.2020.05.013] [PMID: 32668227]
[8]
Dou, Z.; Ghosh, K.; Vizioli, M.G.; Zhu, J.; Sen, P.; Wangen-steen, K.J.; Simithy, J.; Lan, Y.; Lin, Y.; Zhou, Z.; Capell, B.C.; Xu, C.; Xu, M.; Kieckhaefer, J.E.; Jiang, T.; Shoshkes-Carmel, M.; Tanim, K.M.A.A.; Barber, G.N.; Seykora, J.T.; Millar, S.E.; Kaestner, K.H.; Garcia, B.A.; Adams, P.D.; Ber-ger, S.L. Cytoplasmic chromatin triggers inflammation in se-nescence and cancer. Nature, 2017, 550(7676), 402-406.
[http://dx.doi.org/10.1038/nature24050] [PMID: 28976970]
[http://dx.doi.org/10.1038/nature24050] [PMID: 28976970]
[9]
Li, X.D.; Wu, J.; Gao, D.; Wang, H.; Sun, L.; Chen, Z.J. Pivot-al roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science, 2013, 341(6152), 1390-1394.
[http://dx.doi.org/10.1126/science.1244040] [PMID: 23989956]
[http://dx.doi.org/10.1126/science.1244040] [PMID: 23989956]
[10]
Konno, H.; Yamauchi, S.; Berglund, A.; Putney, R.M.; Mulé, J.J.; Barber, G.N. Suppression of STING signaling through ep-igenetic silencing and missense mutation impedes DNA dam-age mediated cytokine production. Oncogene, 2018, 37(15), 2037-2051.
[http://dx.doi.org/10.1038/s41388-017-0120-0] [PMID: 29367762]
[http://dx.doi.org/10.1038/s41388-017-0120-0] [PMID: 29367762]
[11]
Højfeldt, J.W.; Agger, K.; Helin, K. Histone lysine demethyl-ases as targets for anticancer therapy. Nat. Rev. Drug Discov., 2013, 12(12), 917-930.
[http://dx.doi.org/10.1038/nrd4154] [PMID: 24232376]
[http://dx.doi.org/10.1038/nrd4154] [PMID: 24232376]
[12]
Arifuzzaman, S.; Khatun, M.R.; Khatun, R. Emerging of ly-sine demethylases (KDMs): From pathophysiological insights to novel therapeutic opportunities. Biomed. Pharmacother., 2020, 129, 110392.
[http://dx.doi.org/10.1016/j.biopha.2020.110392] [PMID: 32574968]
[http://dx.doi.org/10.1016/j.biopha.2020.110392] [PMID: 32574968]
[13]
Blair, L.P.; Cao, J.; Zou, M.R.; Sayegh, J.; Yan, Q. Epigenetic regulation by lysine demethylase 5 (KDM5) enzymes in can-cer. Cancers (Basel), 2011, 3(1), 1383-1404.
[http://dx.doi.org/10.3390/cancers3011383] [PMID: 21544224]
[http://dx.doi.org/10.3390/cancers3011383] [PMID: 21544224]
[14]
Dorosz, J.; Kristensen, L.H.; Aduri, N.G.; Mirza, O.; Lousen, R.; Bucciarelli, S.; Mehta, V.; Sellés-Baiget, S.; Solbak, S.M.Ø.; Bach, A.; Mesa, P.; Hernandez, P.A.; Montoya, G.; Nguyen, T.T.T.N.; Rand, K.D.; Boesen, T.; Gajhede, M. Mo-lecular architecture of the Jumonji C family histone demethyl-ase KDM5B. Sci. Rep., 2019, 9(1), 4019.
[http://dx.doi.org/10.1038/s41598-019-40573-y] [PMID: 30858420]
[http://dx.doi.org/10.1038/s41598-019-40573-y] [PMID: 30858420]
[15]
Mitsui, E.; Yoshida, S.; Shinoda, Y.; Matsumori, Y.; Tsujii, H.; Tsuchida, M.; Wada, S.; Hasegawa, M.; Ito, A.; Mino, K.; Onuki, T.; Yoshida, M.; Sasaki, R.; Mizukami, T. Identifica-tion of ryuvidine as a KDM5A inhibitor. Sci. Rep., 2019, 9(1), 9952.
[http://dx.doi.org/10.1038/s41598-019-46346-x] [PMID: 31289306]
[http://dx.doi.org/10.1038/s41598-019-46346-x] [PMID: 31289306]
[16]
Plch, J.; Hrabeta, J.; Eckschlager, T. KDM5 demethylases and their role in cancer cell chemoresistance. Int. J. Cancer, 2019, 144(2), 221-231.
[http://dx.doi.org/10.1002/ijc.31881] [PMID: 30246379]
[http://dx.doi.org/10.1002/ijc.31881] [PMID: 30246379]
[17]
Hinohara, K.; Wu, H.J.; Vigneau, S.; McDonald, T.O.; Iga-rashi, K.J.; Yamamoto, K.N.; Madsen, T.; Fassl, A.; Egri, S.B.; Papanastasiou, M.; Ding, L.; Peluffo, G.; Cohen, O.; Kales, S.C.; Lal-Nag, M.; Rai, G.; Maloney, D.J.; Jadhav, A.; Simeonov, A.; Wagle, N.; Brown, M.; Meissner, A.; Sicinski, P.; Jaffe, J.D.; Jeselsohn, R.; Gimelbrant, A.A.; Michor, F.; Polyak, K. KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell, 2018, 34(6), 939-953.e9.
[http://dx.doi.org/10.1016/j.ccell.2018.10.014] [PMID: 30472020]
[http://dx.doi.org/10.1016/j.ccell.2018.10.014] [PMID: 30472020]
[18]
de Queiroz, N.M.G.P.; Xia, T.; Konno, H.; Barber, G.N. Ovar-ian cancer cells commonly exhibit defective STING signaling which affects sensitivity to viral oncolysis. Mol. Cancer Res., 2019, 17(4), 974-986.
[http://dx.doi.org/10.1158/1541-7786.MCR-18-0504] [PMID: 30587523]
[http://dx.doi.org/10.1158/1541-7786.MCR-18-0504] [PMID: 30587523]
[19]
Kitajima, S.; Ivanova, E.; Guo, S.; Yoshida, R.; Campisi, M.; Sundararaman, S.K.; Tange, S.; Mitsuishi, Y.; Thai, T.C.; Ma-suda, S.; Piel, B.P.; Sholl, L.M.; Kirschmeier, P.T.; Paweletz, C.P.; Watanabe, H.; Yajima, M.; Barbie, D.A. Suppression of sting associated with LKB1 loss in KRAS-driven lung canceR. Cancer Discov., 2019, 9(1), 34-45.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0689] [PMID: 30297358]
[http://dx.doi.org/10.1158/2159-8290.CD-18-0689] [PMID: 30297358]
[20]
Civril, F.; Deimling, T.; de Oliveira Mann, C.C.; Ablasser, A.; Moldt, M.; Witte, G.; Hornung, V.; Hopfner, K.P. Structural mechanism of cytosolic DNA sensing by cGAS. Nature, 2013, 498(7454), 332-337.
[http://dx.doi.org/10.1038/nature12305] [PMID: 23722159]
[http://dx.doi.org/10.1038/nature12305] [PMID: 23722159]
[21]
Kwon, J.; Bakhoum, S.F. The cytosolic DNA-sensing cGAS-sting pathway in cancer. Cancer Discov., 2020, 10(1), 26-39.
[http://dx.doi.org/10.1158/2159-8290.CD-19-0761] [PMID: 31852718]
[http://dx.doi.org/10.1158/2159-8290.CD-19-0761] [PMID: 31852718]
[22]
Ahn, J.; Konno, H.; Barber, G.N. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene, 2015, 34(41), 5302-5308.
[http://dx.doi.org/10.1038/onc.2014.457] [PMID: 25639870]
[http://dx.doi.org/10.1038/onc.2014.457] [PMID: 25639870]
[23]
Ahn, J.; Xia, T.; Konno, H.; Konno, K.; Ruiz, P.; Barber, G.N. Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun., 2014, 5, 5166.
[http://dx.doi.org/10.1038/ncomms6166] [PMID: 25300616]
[http://dx.doi.org/10.1038/ncomms6166] [PMID: 25300616]
[24]
Woo, S.R.; Fuertes, M.B.; Corrales, L.; Spranger, S.; Furdyna, M.J.; Leung, M.Y.; Duggan, R.; Wang, Y.; Barber, G.N.; Fitz-gerald, K.A.; Alegre, M.L.; Gajewski, T.F. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity, 2014, 41(5), 830-842.
[http://dx.doi.org/10.1016/j.immuni.2014.10.017] [PMID: 25517615]
[http://dx.doi.org/10.1016/j.immuni.2014.10.017] [PMID: 25517615]
[25]
Barber, G.N. STING: Infection, inflammation and cancer. Nat. Rev. Immunol., 2015, 15(12), 760-770.
[http://dx.doi.org/10.1038/nri3921] [PMID: 26603901]
[http://dx.doi.org/10.1038/nri3921] [PMID: 26603901]
[26]
Liang, D.; Xiao-Feng, H.; Guan-Jun, D.; Er-Ling, H.; Sheng, C.; Ting-Ting, W.; Qin-Gang, H.; Yan-Hong, N.; Ya-Yi, H. Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal. Biochim. Biophys. Acta, 2015, 1852(11), 2494-2503.
[http://dx.doi.org/10.1016/j.bbadis.2015.08.011] [PMID: 26303640]
[http://dx.doi.org/10.1016/j.bbadis.2015.08.011] [PMID: 26303640]
[27]
Schadt, L.; Sparano, C.; Schweiger, N.A.; Silina, K.; Cecconi, V.; Lucchiari, G.; Yagita, H.; Guggisberg, E.; Saba, S.; Nas-cakova, Z.; Barchet, W.; van den Broek, M. Cancer-cell-intrinsic cgas expression mediates tumor immunogenicity. Cell Rep., 2019, 29(5), 1236-1248.e7.
[http://dx.doi.org/10.1016/j.celrep.2019.09.065] [PMID: 31665636]
[http://dx.doi.org/10.1016/j.celrep.2019.09.065] [PMID: 31665636]
[28]
Peng, D.; Lin, B.; Xie, M.; Zhang, P.; Guo, Q.; Li, Q.; Gu, Q.; Yang, S.; Sen, L. Histone demethylase KDM5A promotes tu-morigenesis of osteosarcoma tumor. Cell Death Discov., 2021, 7(1), 9.
[http://dx.doi.org/10.1038/s41420-020-00396-7] [PMID: 33436536]
[http://dx.doi.org/10.1038/s41420-020-00396-7] [PMID: 33436536]
[29]
Hao, F. Systemic Profiling of KDM5 Subfamily Signature in Non-Small-Cell Lung Cancer. Int. J. Gen. Med., 2021, 14, 7259-7275.
[http://dx.doi.org/10.2147/IJGM.S329733] [PMID: 34737620]
[http://dx.doi.org/10.2147/IJGM.S329733] [PMID: 34737620]
[30]
Dvorak, H.F. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med., 1986, 315(26), 1650-1659.
[http://dx.doi.org/10.1056/NEJM198612253152606] [PMID: 3537791]
[http://dx.doi.org/10.1056/NEJM198612253152606] [PMID: 3537791]
[31]
Mackenzie, K.J.; Carroll, P.; Martin, C.A.; Murina, O.; Fluteau, A.; Simpson, D.J.; Olova, N.; Sutcliffe, H.; Rainger, J.K.; Leitch, A.; Osborn, R.T.; Wheeler, A.P.; Nowotny, M.; Gilbert, N.; Chandra, T.; Reijns, M.A.M.; Jackson, A.P. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature, 2017, 548(7668), 461-465.
[http://dx.doi.org/10.1038/nature23449] [PMID: 28738408]
[http://dx.doi.org/10.1038/nature23449] [PMID: 28738408]
[32]
Motwani, M.; Pesiridis, S.; Fitzgerald, K.A. DNA sensing by the cGAS-STING pathway in health and disease. Nat. Rev. Genet., 2019, 20(11), 657-674.
[http://dx.doi.org/10.1038/s41576-019-0151-1] [PMID: 31358977]
[http://dx.doi.org/10.1038/s41576-019-0151-1] [PMID: 31358977]
[33]
Bai, J.; Liu, F. The cGAS-cGAMP-STING pathway: A mo-lecular link between immunity and metabolism. Diabetes, 2019, 68(6), 1099-1108.
[http://dx.doi.org/10.2337/dbi18-0052] [PMID: 31109939]
[http://dx.doi.org/10.2337/dbi18-0052] [PMID: 31109939]
[34]
Corrales, L.; Glickman, L.H.; McWhirter, S.M.; Kanne, D.B.; Sivick, K.E.; Katibah, G.E.; Woo, S.R.; Lemmens, E.; Banda, T.; Leong, J.J.; Metchette, K.; Dubensky, T.W., Jr; Gajewski, T.F. Direct activation of STING in the tumor microenviron-ment leads to potent and systemic tumor regression and im-munity. Cell Rep., 2015, 11(7), 1018-1030.
[http://dx.doi.org/10.1016/j.celrep.2015.04.031] [PMID: 25959818]
[http://dx.doi.org/10.1016/j.celrep.2015.04.031] [PMID: 25959818]
[35]
Kitai, Y.; Kawasaki, T.; Sueyoshi, T.; Kobiyama, K.; Ishii, K.J.; Zou, J.; Akira, S.; Matsuda, T.; Kawai, T. DNA-containing exosomes derived from cancer cells treated with topotecan activate a STING-dependent pathway and reinforce antitumor immunity. J. Immunol., 2017, 198(4), 1649-1659.
[http://dx.doi.org/10.4049/jimmunol.1601694] [PMID: 28069806]
[http://dx.doi.org/10.4049/jimmunol.1601694] [PMID: 28069806]
[36]
Vance, R.E. Cytosolic DNA sensing: The field narrows. Immunity, 2016, 45(2), 227-228.
[http://dx.doi.org/10.1016/j.immuni.2016.08.006] [PMID: 27533006]
[http://dx.doi.org/10.1016/j.immuni.2016.08.006] [PMID: 27533006]
[37]
Eaglesham, J.B.; Pan, Y.; Kupper, T.S.; Kranzusch, P.J. Viral and metazoan poxins are cGAMP-specific nucleases that re-strict cGAS-STING signalling. Nature, 2019, 566(7743), 259-263.
[http://dx.doi.org/10.1038/s41586-019-0928-6] [PMID: 30728498]
[http://dx.doi.org/10.1038/s41586-019-0928-6] [PMID: 30728498]
[38]
Marcus, A.; Mao, A.J.; Lensink-Vasan, M.; Wang, L.; Vance, R.E.; Raulet, D.H. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity, 2018, 49(4), 754-763.e4.
[http://dx.doi.org/10.1016/j.immuni.2018.09.016] [PMID: 30332631]
[http://dx.doi.org/10.1016/j.immuni.2018.09.016] [PMID: 30332631]
[39]
Hopfner, K.P.; Hornung, V. Molecular mechanisms and cellu-lar functions of cGAS-STING signalling. Nat. Rev. Mol. Cell Biol., 2020, 21(9), 501-521.
[http://dx.doi.org/10.1038/s41580-020-0244-x] [PMID: 32424334]
[http://dx.doi.org/10.1038/s41580-020-0244-x] [PMID: 32424334]
[40]
Zong, J.; Keskinov, A.A.; Shurin, G.V.; Shurin, M.R. Tumor-derived factors modulating dendritic cell function. Cancer Immunol. Immunother., 2016, 65(7), 821-833.
[http://dx.doi.org/10.1007/s00262-016-1820-y] [PMID: 26984847]
[http://dx.doi.org/10.1007/s00262-016-1820-y] [PMID: 26984847]
[41]
Glück, S.; Guey, B.; Gulen, M.F.; Wolter, K.; Kang, T.W.; Schmacke, N.A.; Bridgeman, A.; Rehwinkel, J.; Zender, L.; Ablasser, A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol., 2017, 19(9), 1061-1070.
[http://dx.doi.org/10.1038/ncb3586] [PMID: 28759028]
[http://dx.doi.org/10.1038/ncb3586] [PMID: 28759028]
[42]
Ranoa, D.R.E.; Widau, R.C.; Mallon, S.; Parekh, A.D.; Nico-lae, C.M.; Huang, X.; Bolt, M.J.; Arina, A.; Parry, R.; Kron, S.J.; Moldovan, G.L.; Khodarev, N.N.; Weichselbaum, R.R. STING promotes homeostasis via regulation of cell prolifera-tion and chromosomal stability. Cancer Res., 2019, 79(7), 1465-1479.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-1972] [PMID: 30482772]
[http://dx.doi.org/10.1158/0008-5472.CAN-18-1972] [PMID: 30482772]
[43]
Song, S.; Peng, P.; Tang, Z.; Zhao, J.; Wu, W.; Li, H.; Shao, M.; Li, L.; Yang, C.; Duan, F.; Zhang, M.; Zhang, J.; Wu, H.; Li, C.; Wang, X.; Wang, H.; Ruan, Y.; Gu, J. Decreased ex-pression of STING predicts poor prognosis in patients with gastric cancer. Sci. Rep., 2017, 7, 39858.
[http://dx.doi.org/10.1038/srep39858] [PMID: 28176788]
[http://dx.doi.org/10.1038/srep39858] [PMID: 28176788]
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