Abstract
Objective
Acute myeloid leukemia (AML) is a highly heterogeneous and recurrent hematological malignancy. Despite the emergence of novel chemotherapy drugs, AML patients’ complete remission (CR) remains unsatisfactory. Consequently, it is imperative to discover new therapeutic targets or medications to treat AML. Such epigenetic changes like DNA methylation and histone modification play vital roles in AML. Peptidylarginine deminase (PAD) is a protein family of histone demethylases, among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients, thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets.
Methods
AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A). The AML cell lines were effectively induced into apoptosis by BB-Cl-A. However, the PAD4-specific inhibitor GSK484 did not.
Results
PAD2 played a significant role in AML. Furthermore, we found that BB-Cl-A could activate the endoplasmic reticulum (ER) stress response, as evidenced by an increase in phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). As a result of the ER stress activation, the BB-Cl-A effectively induced apoptosis in the AML cells.
Conclusion
Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention. Therefore, targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.
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References
Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med, 2015, 373(12): 1136–1152
Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol, 2018, 93(10): 1267–1291
Bewersdorf JP, Shallis R, Stahl M, et al. Epigenetic therapy combinations in acute myeloid leukemia: what are the options. Ther Adv Hematol, 2019, 10: 2040620718816 698
Alqahtani A, Choucair K, Ashraf M, et al. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. Future Sci OA, 2019, 5(3): FSO372
Cheung N, Fung TK, Zeisig BB, et al. Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia. Cancer Cell, 2016, 29(1): 32–48
Nguyen AT, Taranova O, He J, et al. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood, 2011, 117(25): 6912–6922
San Jose-Eneriz E, Gimenez-Camino N, Agirre X, et al. HDAC Inhibitors in Acute Myeloid Leukemia. Cancers (Basel), 2019, 11(11): 1794
Tarighat SS, Santhanam R, Frankhouser D, et al. The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia, 2016, 30(4): 789–799
Gambacorta V, Gnani D, Vago L, et al. Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects. Front Cell Dev Biol, 2019, 7: 207
Wingelhofer B, Somervaille TCP. Emerging Epigenetic Therapeutic Targets in Acute Myeloid Leukemia. Front Oncol, 2019, 9: 850
Mohanan S, Cherrington BD, Horibata S, et al. Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis. Biochem Res Int, 2012, 2012: 895343
Chang X, Han J. Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog, 2006, 45(3): 183–196
Nachat R, Mechin MC, Takahara H, et al. Peptidylarginine deiminase isoforms 1–3 are expressed in the epidermis and involved in the deimination of K1 and filaggrin. J Invest Dermatol, 2005, 124(2): 384–393
Yurttas P, Vitale AM, Fitzhenry RJ, et al. Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo. Development, 2008, 135(15): 2627–2636
Wang Y, Wysocka J, Sayegh J, et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science, 2004, 306(5694): 279–283
Song S, Xiang Z, Li J, et al. A Novel Citrullinated Modification of Histone 3 and Its Regulatory Mechanisms Related to IPO-38 Antibody-Labeled Protein. Front Oncol, 2019, 9: 304
Falcao AM, Meijer M, Scaglione A, et al. PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination. Cell Rep, 2019, 27(4): 1090–1102.e10
McElwee JL, Mohanan S, Griffith OL, et al. Identification of PADI2 as a potential breast cancer biomarker and therapeutic target. BMC Cancer, 2012, 12: 500
Wang L, Song G, Zhang X, et al. PADI2-Mediated Citrullination Promotes Prostate Cancer Progression. Cancer Res, 2017, 77(21): 5755–5768
Chang X, Fang K. PADI4 and tumourigenesis. Cancer Cell Int, 2010, 10: 7
Moshkovich N, Ochoa HJ, Tang B, et al. Peptidylarginine Deiminase IV Regulates Breast Cancer Stem Cells via a Novel Tumor Cell-Autonomous Suppressor Role. Cancer Res, 2020, 80(1): 2125–2137
Ledet MM, Anderson R, Harman R, et al. BB-Cl-Amidine as a novel therapeutic for canine and feline mammary cancer via activation of the endoplasmic reticulum stress pathway. BMC Cancer, 2018, 18(1): 412
Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta, 2013, 1833(12): 3460–3470
Liu LD, Zhang ZW, Ma YC, et al. Down-regulation of PADI2 prevents proliferation and epithelial-mesenchymal transition in ovarian cancer through inhibiting JAK2/STAT3 pathway in vitro and in vivo, alone or in combination with Olaparib. J Transl Med, 2020, 18(1): 357
Xue T, Liu X, Zhang M, et al. PADI2-Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2-BP1-Mediated SOX2 mRNA Stability in Endometrial Cancer. Adv Sci (Weinh), 2021, 8(6): 2002831
Wang Y, Li P, Wang S, et al. Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J Biol Chem, 2012, 287(31): 25941–25953
Wang S, Chen XA, Hu J, et al. ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells. Mol Cancer Ther, 2015, 14(4): 877–888
Gu YH, Wang Y, Bai Y, et al. Endoplasmic reticulum stress and apoptosis via PERK-eIF2alpha-CHOP signaling in the methamphetamine-induced chronic pulmonary injury. Environ Toxicol Pharmacol, 2017, 49: 194–201
Masciarelli S, Capuano E, Ottone T, et al. Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML. Blood Adv, 2019, 3(24): 4155–4160
Li P, Li M, Lindberg MR, et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med, 2010, 207(9): 1853–1862
Yu Y, Su K. Neutrophil Extracellular Traps and Systemic Lupus Erythematosus. J Clin Cell Immunol, 2013, 4: 139
Knight JS, Subramanian V, O’Dell AA, et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis, 2015, 74(12): 2199–2206
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This work was supported by the National Natural Science Foundation of China (No. 81972564).
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Sun, Yn., Ma, Yn., Jia, Xq. et al. Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells. CURR MED SCI 42, 958–965 (2022). https://doi.org/10.1007/s11596-022-2637-x
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DOI: https://doi.org/10.1007/s11596-022-2637-x