SENP3 Promotes Mantle Cell Lymphoma Development through Regulating Wnt10a Expression

Abstract

Objective

SUMO-specific protease 3 (SENP3), a member of the SUMO-specific protease family, reverses the SUMOylation of SUMO-2/3 conjugates. Dysregulation of SENP3 has been proven to be involved in the development of various tumors. However, its role in mantle cell lymphoma (MCL), a highly aggressive lymphoma, remains unclear. This study was aimed to elucidate the effect of SENP3 in MCL.

Methods

The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR, Western blotting or immunohistochemistry. MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs. Cell proliferation was assessed by CCK-8 assay, and cell apoptosis was determined by flow cytometry. mRNA sequencing (mRNA-seq) was used to investigate the underlying mechanism of SENP3 knockdown on MCL development. A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo.

Results

SENP3 was upregulated in MCL patient samples and cells. Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis. Meanwhile, the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown. Furthermore, the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model.

Conclusion

SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

Keywords

mantle cell lymphoma / SENP3 / cell proliferation / apoptosis

References

[1]	Wilson MR, Barrett A, Cheah CY, et al. How I manage mantle cell lymphoma: indolent versus aggressive disease. Br J Haematol, 2023,201(2):185–198
[2]	Kumar A, Sha F, Toure A, et al. Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: progressive shortening in response duration and survival after each relapse. Blood Cancer J, 2019,9(6):50
[3]	Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol, 2019,94(6):710–725
[4]	Zhang Y, Ma Y, Wu G, et al. SENP1 promotes MCL pathogenesis through regulating JAK-STAT5 pathway and SOCS2 expression. Cell Death Discov, 2021,7(1):192
[5]	Fernàndez V, Hartmann E, Ott G, et al. Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol, 2005,23(26):6364–6369
[6]	Klener P. Mantle cell lymphoma: insights into therapeutic targets at the preclinical level. Expert Opin Ther Targets, 2020,24(10):1029–1045
[7]	Zhang H, Chen Z, Miranda RN, et al. TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy. Cancer Res, 2016,76(21):6410–6423
[8]	Kunz K, Piller T, Müller S. SUMO-specific proteases and isopeptidases of the SENP family at a glance. J Cell Sci, 2018,131(6):jcs211904
[9]	Gareau JR, Lima CD. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol, 2010,11(12):861–871
[10]	Li J, Liang L, Jiang L, et al. Viral RNA-binding ability conferred by SUMOylation at PB1 K612 of influenza A virus is essential for viral pathogenesis and transmission. PLoS Pathog, 2021,17(2):e1009336
[11]	Stokes S, Almire F, Tatham MH, et al. The SUMOylation pathway suppresses arbovirus replication in Aedes aegypti cells. PLoS Pathog, 2020,16(12):e1009134
[12]	Chang H, Yeh E. SUMO: From Bench to Bedside. Physiol Rev, 2020,100(4):1599–1619
[13]	Han Y, Huang C, Sun X, et al. SENP3-mediated deconjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress. J Biol Chem, 2010,285(17):12906–12915
[14]	Huang C, Han Y, Wang Y, et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. Embo J, 2009,28(18):2748–2762
[15]	Nishida T, Yamada Y. The nucleolar SUMO-specific protease SMT3IP1/SENP3 attenuates Mdm2-mediated p53 ubiquitination and degradation. Biochem Biophys Res Commun, 2011,406(2):285–291
[16]	Zhou Z, Wang M, Li J, et al. SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer. Oncogene, 2016,35(45):5826–5838
[17]	Ren YH, Liu KJ, Wang M, et al. De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells. Oncotarget, 2014,5(16):7093–7104
[18]	Yan S, Sun X, Xiang B, et al. Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90. Embo J, 2010,29(22):3773–3786
[19]	Louche A, Blanco A, Lacerda TLS, et al. Brucella effectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins. Nat Commun, 2023,14(1):102
[20]	Wu X, Li JH, Xu L, et al. SUMO specific peptidase 3 halts pancreatic ductal adenocarcinoma metastasis via deSUMOylating DKC1. Cell Death Differ, 2023,30(7):1742–1756
[21]	Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood, 2011,117(1):26–38
[22]	Vega F, Davuluri Y, Cho-Vega JH, et al. Side population of a murine mantle cell lymphoma model contains tumour-initiating cells responsible for lymphoma maintenance and dissemination. J Cell Mol Med, 2010,14(6B):1532–1545
[23]	Chan WK, Williams J, Sorathia K, et al. A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models. Exp Hematol Oncol, 2023,12(1):79
[24]	Sloan SL, Brown F, Long M, et al. PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma. Blood, 2023,142(10):887–902
[25]	Yeh ET, Gong L, Kamitani T. Ubiquitin-like proteins: new wines in new bottles. Gene, 2000,248(1–2):1–14
[26]	Hang J, Dasso M. Association of the human SUMO-1 protease SENP2 with the nuclear pore. J Biol Chem, 2002,277(22):19961–19966
[27]	Eifler K, Vertegaal ACO. SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer. Trends Biochem Sci, 2015,40(12):779–793
[28]	Zhao Y, Yang B, Chen D, et al. Combined identification of ARID1A, CSMD1, and SENP3 as effective prognostic biomarkers for hepatocellular carcinoma. Aging (Albany NY), 2021,13(3):4696–4712
[29]	Tong Y, Zhang Z, Cheng Y, et al. Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression. Cell Death Dis, 2022,13(4):413
[30]	Long X, Zhao B, Lu W, et al. The Critical Roles of the SUMO-Specific Protease SENP3 in Human Diseases and Clinical Implications. Front Physiol, 2020,11:558220
[31]	Gelebart P, Anand M, Armanious H, et al. Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood, 2008,112(13):5171–5179
[32]	Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer, 2008,8(5):387–398
[33]	Cao X, Wang X, Zhang W, et al. WNT10A induces apoptosis of senescent synovial resident stem cells through Wnt/calcium pathway-mediated HDAC5 phosphorylation in OAjoints. Bone, 2021,150:116006
[34]	Wang J, Yang Q, Tang M, et al. Validation and analysis of expression, prognosis and immune infiltration of WNT gene family in non-small cell lung cancer. Front Oncol, 2022,12:911316
[35]	Cesarato N, Schwieger-Briel A, Gossmann Y, et al. Short anagen hair syndrome: Association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss. Br J Dermatol, 2023,189(6):741–749
[36]	Sun X, Fang J, Ye F, et al. Diffuse Large B-Cell Lymphoma Promotes Endothelial-to-Mesenchymal Transition via WNT10A/Beta-Catenin/Snail Signaling. Front Oncol, 2022,12:871788