KAT8 Catalyzes the Acetylation of SEPP1 at Lysine 247/249 and Modulates the Activity of CD8 T Cells Via LRP8 to Promote Anti-tumor Immunity in Pancreatic Cancer

Overview

Journal Cell Biosci

Publisher Biomed Central

Specialty Biology

Date 2025 Feb 19

PMID 39972392

Authors

Zhongfei Zhu

Gang Nie

Xiaobo Peng

Xianbao Zhan

Dan Ding

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic cancer (PC) remains one of the most lethal malignancies with unfavorable prognosis globally. Bioinformatics analysis predicted that SEPP1 was low expressed in PC and related to tumor immune microenvironment, but its biological function was still unclear.

Methods: PC xenograft and liver metastasis mouse models, as well as PC cell-MDSCs co-culture system, were established for in vivo and in vitro studies, respectively. The expression and localization of key molecules were detected by qRT-PCR, western blot, immunohistochemistry and immunofluorescence. Flow cytometry was employed to assess the abundance of immune cells and cell apoptosis. The interactions among KAT8, SEPP1 and LRP8 were detected by co-IP. Cell viability, migration and invasion were monitored by CCK-8 and transwell assays.

Results: SEPP1 was downregulated in pancreatic tumors, and it was positively correlated with the abundance of CD8 T cells. In vivo overexpression of SEPP1 impaired PC tumor growth and liver metastasis via modulating the abundance of CD8 T cell and MDSCs. KAT8 upregulated SEPP1 transcription and protein level via catalyzing the acetylation at K247/249 on SEPP1, and SEPP1 impaired MDSCs survival via its receptor LRP8, thus regulating CD8 T cell-mediated immune responses in PC. In vivo studies further revealed that SEPP1 recombinant protein enhanced the efficacy of anti-PD-1 therapy in PC xenograft mouse model.

Conclusion: KAT8 catalyzed the acetylation of SEPP1 at K247/249 and modulated the activity of CD8 T cells via LRP8 to promote anti-tumor immunity in PC.

References

Soares K, Rucki A, Kim V, Foley K, Solt S, Wolfgang C . TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget. 2015; 6(40):43005-15. PMC: 4767487. DOI: 10.18632/oncotarget.5656. View

Murakami T, Hiroshima Y, Matsuyama R, Homma Y, Hoffman R, Endo I . Role of the tumor microenvironment in pancreatic cancer. Ann Gastroenterol Surg. 2019; 3(2):130-137. PMC: 6422798. DOI: 10.1002/ags3.12225. View

Saito Y, Takahashi K . Characterization of selenoprotein P as a selenium supply protein. Eur J Biochem. 2002; 269(22):5746-51. DOI: 10.1046/j.1432-1033.2002.03298.x. View

Zhang X, Yang Z, An Y, Liu Y, Wei Q, Xu F . Clinical benefits of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer: a systematic review and meta-analysis. World J Surg Oncol. 2022; 20(1):93. PMC: 8944161. DOI: 10.1186/s12957-022-02549-7. View

Arteel G, Mostert V, Oubrahim H, Briviba K, Abel J, Sies H . Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biol Chem. 1998; 379(8-9):1201-5. View

Li X, Wu L, Corsa C, Kunkel S, Dou Y . Two mammalian MOF complexes regulate transcription activation by distinct mechanisms. Mol Cell. 2009; 36(2):290-301. PMC: 2768600. DOI: 10.1016/j.molcel.2009.07.031. View

Radzisheuskaya A, Shliaha P, Grinev V, Shlyueva D, Damhofer H, Koche R . Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcription and cellular homeostasis. Mol Cell. 2021; 81(8):1749-1765.e8. PMC: 8056186. DOI: 10.1016/j.molcel.2021.02.012. View

Feng M, Xiong G, Cao Z, Yang G, Zheng S, Song X . PD-1/PD-L1 and immunotherapy for pancreatic cancer. Cancer Lett. 2017; 407:57-65. DOI: 10.1016/j.canlet.2017.08.006. View

Burk R, Hill K, Olson G, Weeber E, Motley A, Winfrey V . Deletion of apolipoprotein E receptor-2 in mice lowers brain selenium and causes severe neurological dysfunction and death when a low-selenium diet is fed. J Neurosci. 2007; 27(23):6207-11. PMC: 6672153. DOI: 10.1523/JNEUROSCI.1153-07.2007. View

10.

Wang W, Shen Y, Zhang P, Liu L, Sha X, Li H . Histone acetylation modification regulator-mediated tumor microenvironment infiltration characteristics and prognostic model of lung adenocarcinoma patients. J Thorac Dis. 2022; 14(10):3886-3902. PMC: 9641363. DOI: 10.21037/jtd-22-1000. View

11.

Vargas F, Furness A, Solomon I, Joshi K, Mekkaoui L, Lesko M . Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity. 2017; 46(4):577-586. PMC: 5437702. DOI: 10.1016/j.immuni.2017.03.013. View

12.

Huber M, Brehm C, Gress T, Buchholz M, Alashkar Alhamwe B, Pogge von Strandmann E . The Immune Microenvironment in Pancreatic Cancer. Int J Mol Sci. 2020; 21(19). PMC: 7583843. DOI: 10.3390/ijms21197307. View

13.

Chen L, Han X . Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015; 125(9):3384-91. PMC: 4588282. DOI: 10.1172/JCI80011. View

14.

Han Y, Liu D, Li L . PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020; 10(3):727-742. PMC: 7136921. View

15.

Xu Y, Liao W, Luo Q, Yang D, Pan M . Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma. Front Immunol. 2022; 13:761046. PMC: 8821108. DOI: 10.3389/fimmu.2022.761046. View

16.

Murawaki Y, Tsuchiya H, Kanbe T, Harada K, Yashima K, Nozaka K . Aberrant expression of selenoproteins in the progression of colorectal cancer. Cancer Lett. 2007; 259(2):218-30. DOI: 10.1016/j.canlet.2007.10.019. View

17.

Yuan Z, Guan Y, Chatterjee D, Chin Y . Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005; 307(5707):269-73. DOI: 10.1126/science.1105166. View

18.

Stromnes I, Brockenbrough J, Izeradjene K, Carlson M, Cuevas C, Simmons R . Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut. 2014; 63(11):1769-81. PMC: 4340484. DOI: 10.1136/gutjnl-2013-306271. View

19.

Zhang X, Lao M, Xu J, Duan Y, Yang H, Li M . Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors. J Immunother Cancer. 2022; 10(3). PMC: 8906048. DOI: 10.1136/jitc-2021-003982. View

20.

Huai W, Liu X, Wang C, Zhang Y, Chen X, Chen X . Correction: KAT8 selectively inhibits antiviral immunity by acetylating IRF3. J Exp Med. 2019; 216(4):1001. PMC: 6446876. DOI: 10.1084/jem.2018177303182019c. View