Improving TRAIL-induced apoptosis in cancers by interfering with histone modifications

Abstract

Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription. Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription. In this review, we provide an overview of recent studies on the role of histone modifications in carcinogenesis. Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are well-considered as promising anti-tumour therapies, we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers. In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.

Keywords

Epigenetics / histone modification / tumor necrosis factor-related apoptosis-inducing ligand / selective epigenetic inhibitors / apoptosis

References

[1] Dawson MA.Cancer epigenetics: From mechanism to therapy..Cell2012;150:12-27

[2] Luger K,Tremethick DJ.New insights into nucleosome and chromatin structure: an ordered state or a disordered affair?.Nat Rev Mol Cell Biol2012;13:436-47 PMCID:PMC3408961

[3] Herbst RS,Kurzrock R,O’Dwyer PJ.Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer..J Clin Oncol2010;28:2839-46

[4] Wong SHM,Fang CM,Chuah LH.The TRAIL to cancer therapy: Hindrances and potential solutions..Crit Rev Oncol Hematol2019;143:81-94

[5] Fulton MD,Zheng YG.Mechanisms and Inhibitors of Histone Arginine Methylation..Chem Rec2018;18:1792-807 PMCID:PMC6348102

[6] Di Lorenzo A.Histone arginine methylation..FEBS Lett2011;585:2024-31 PMCID:PMC3409563

[7] Song S.Progression on citrullination of proteins in gastrointestinal cancers..Front Oncol2019;9:1-6 PMCID:PMC6357933

[8] Hyun K,Park K.Writing, erasing and reading histone lysine methylations..Exp Mol Med2017;49: PMCID:PMC6130214

[9] Sanaei M.Histone deacetylases and histone deacetylase inhibitors: molecular mechanisms of action in various cancers..Adv Biomed Res2019;8:63 PMCID:PMC6839273

[10] Audia JE.Histone modifications and cancer..Cold Spring Harb Perspect Biol2016;8:a019521 PMCID:PMC4817802

[11] Kebede AF,Shahidian LZ,Richter F.Histone propionylation is a mark of active chromatin..Nat Struct Mol Biol2017;24:1048-56

[12] Goudarzi A,Huang H,Kwon OK.Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters..Mol Cell2016;62:169-80 PMCID:PMC4850424

[13] Dai L,Montellier E,Chen Y.Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark..Nat Chem Biol2014;10:365-70

[14] Ishiguro T,Kobayashi Y,Kanai M.Malonylation of histone H2A at lysine 119 inhibits Bub1-dependent H2A phosphorylation and chromosomal localization of shugoshin proteins..Sci Rep2018;8:1-10 PMCID:PMC5956101

[15] Wang Y,Liu K,Liu R.KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase..Nature2017;552:273-7 PMCID:PMC5841452

[16] Tan M,Lee S,Yang JS.Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification..Cell2011;146:1016-28 PMCID:PMC3176443

[17] Iberg AN,Cheng D,Michaud-Levesque J.Arginine methylation of the histone H3 tail impedes effector binding..J Biol Chem2008;283:3006-10

[18] Zhao Q,Tan YT,Moritz RL.PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing..Nat Struct Mol Biol2009;16:304-11 PMCID:PMC5120857

[19] Chang B,Zhao Y.JMJD6 is a histone arginine demethylase..Science2007;318:444-7

[20] Webby CJ,Gromak N,Kramer H.JMJD6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing..Science2009;325:90-3

[21] Hong X,White J,Pan CH.Interaction of JMJD6 with single-stranded RNA..Proc Natl Acad Sci U S A2010;107:14568-72 PMCID:PMC2930430

[22] Mantri M,Bagg EA,Butler DS.Crystal structure of the 2-Oxoglutarate- and Fe(II)-dependent lysyl hydroxylase JMJD6..J Mol Biol2010;401:211-22

[23] Li S,Duan X,Du J.JMJD1B demethylates H4R3me2s and H3K9me2 to facilitate gene expression for development of hematopoietic stem and progenitor cells..Cell Rep2018;23:389-403 PMCID:PMC5933860

[24] Hamam HJ.Post-translational modifications in netosis and nets-mediated diseases..Biomolecules2019;9:1-25 PMCID:PMC6723044

[25] Kerimoglu C,Jain G,Burkhardt S.KMT2A and KMT2B mediate memory function by affecting distinct genomic regions..Cell Rep2017;20:538-48

[26] Shi YG.The discovery of histone demethylases..Cold Spring Harb Perspect Biol2013;5:2-4 PMCID:PMC3753710

[27] Chen Y,Tang Y,Sangras B.Lysine propionylation and butyrylation are novel post-translational modifications in histones..Mol Cell Proteomics2007;6:812-9 PMCID:PMC2911958

[28] Xie Z,Dai L,Cheng Z.Lysine succinylation and lysine malonylation in histones..Mol Cell Proteomics2012;11:100-7 PMCID:PMC3418837

[29] Jeusset L.Developing targeted therapies that exploit aberrant histone ubiquitination in cancer..Cells2019;8:165 PMCID:PMC6406838

[30] Cubeñas-Potts C.SUMO: a multifaceted modifier of chromatin structure and function..Dev Cell2013;24:1-12 PMCID:PMC3555686

[31] Rossetto D,Côté J.Histone phosphorylation..Epigenetics2012;7:1098-108

[32] Yang Y.Protein arginine methyltransferases and cancer..Nat Rev Cancer2012;13:37-50

[33] Pal S,Byrd JC,Jacob ST.Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma..EMBO J2007;26:3558-69 PMCID:PMC1949000

[34] Chung J,Tae S,Smith P.Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) Silencing..J Biol Chem2013;288:35534-47 PMCID:PMC3853299

[35] Zhu F,Bates PD,Zhang H.PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells..Leukemia2019;33:2898-911 PMCID:PMC7494157

[36] Chung J,Baiocchi RA.Protein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT/β-catenin and AKT/GSK3β proliferative signaling..J Biol Chem2019;294:7692-710 PMCID:PMC6514641

[37] Alinari L,Yan F,Chung JH.Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation..Blood2015;125:2530-43 PMCID:PMC4400290

[38] Kim YR,Park RY,Bae JA.Differential CARM1 expression in prostate and colorectal cancers..BMC Cancer2010;10:1-13 PMCID:PMC2881889

[39] Takahashi Y,Kawai T,Ito T.Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer..Breast Cancer2012;19:242-52

[40] Zhong J,Zu XY,Yang J.Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma..FEBS J2012;279:316-35

[41] Yoshimatsu M,Hayami S,Tsunoda T.Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers..Int J Cancer2011;128:562-73

[42] Cheung N,Thompson A,So CWE.Protein arginine-methyltransferase-dependent oncogenesis..Nat Cell Biol2007;9:1208-15

[43] Fedoriw A,O’Brien S,Mitchell LH.Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss..Cancer Cell2019;36:100-14.e25

[44] Stein EM,Rizzieri DA,Berdeja JG.The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia..Blood2018;131:2662-9 PMCID:PMC6265654

[45] Waters NJ,Rehlaender BN,Campbell CT.Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target..J Control Release2015;220:758-65

[46] Waters NJ.Preclinical pharmacokinetics and pharmacodynamics of pinometostat (EPZ-5676), a first-in-class, small molecule S-adenosyl methionine competitive inhibitor of DOT1L..Eur J Drug Metab Pharmacokinet2017;42:891-901

[47] Campbell CT,Drubin DA,Maria MJ.Mechanisms of pinometostat (EPZ-5676) treatment-emergent resistance in MLL-rearranged leukemia..Mol. Cancer Ther2017;16:1669-79

[48] Blum KA,Maris M,Goy A.41OA phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma..Ann Oncol2018;29:2018

[49] Wu T, Millar H, Gaffney D, Beke L, Mannens G, et al. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models. Available from: https://cancerres.aacrjournals.org/content/78/13_Supplement/4859. [Last accessed on 17 Sep 2020]

[50] Italiano A,Toulmonde M,Lucchesi C.Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study..Lancet Oncol2018;19:649-59

[51] Knutson SK,Minoshima Y,Huang KC.Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma..Mol Cancer Ther2014;13:842-54

[52] Brach D,Drew A,Motwani V.EZH2 inhibition by tazemetostat results in altered dependency on B-cell activation signaling in DLBCL..Mol Cancer Ther2017;16:2586-97

[53] Kurmasheva RT,Favours E,Kurmashev D.Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program..Pediatr Blood Cancer2017;64: PMCID:PMC5584632

[54] Bauer TM,Martinez-Marti A,Moreno V.Phase I, open-label, dose-escalation study of the safety, pharmacokinetics, pharmacodynamics, and efficacy of GSK2879552 in relapsed/refractory SCLC.J Thorac Oncol2019;14:1828-38

[55] Mohammad HP,Kamat CD,Federowicz KE.A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC..Cancer Cell2015;28:57-69

[56] Rasco D, Tolcher A, Siu LL, Heinhuis K, Postel-Vinay S, et al. A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin’s lymphoma. Available from: https://cancerres.aacrjournals.org/content/77/13_Supplement/CT038. [Last accessed on 17 Sep 2020]

[57] Siu LL,Vinay SP,J Menis FLO.A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumors..nn Oncol2019;30:159

[58] Gerhart S V.,Thompson C,Zhang XP.Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing..Sci Rep2018;8:1-15

[59] Husmann D.Histone lysine methyltransferases in biology and disease..Nat Struc. Mol Biol2019;26:880-9

[60] Arrowsmith CH,Fish PV,Schapira M.Epigenetic protein families: a new frontier for drug discovery..Nat Rev Drug Discov2012;11:384-400

[61] Kuzmichev A,Erdjument-Bromage H,Reinberg D.Histone methyltransferase activity of Zeste protein complex containing the Enhancer associated with a human multiprotein..Genes Dev2002;16:2893-905 PMCID:PMC187479

[62] Li B.EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications..J Hematol Oncol2019;12:118 PMCID:PMC6868783

[63] Lue JK.Emerging EZH2 Inhibitors and Their Application in Lymphoma..Curr Hematol Malig Rep2018;13:369-82

[64] McCabe MT,Ganji G,Halsey WS.Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)..Proc Natl Acad Sci U S A2012;109:2989-94 PMCID:PMC3287005

[65] Mann BS,Cohen MH,Pazdur R.FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma..Oncologist2007;12:1247-52

[66] Lee HZ,Del Valle PL,Saber H.FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma..Clin Cancer Res2015;21:2666-70

[67] Raedler LA.Farydak (Panobinostat): first HDAC inhibitor approved for patients with relapsed multiple myeloma..Am Heal drug benefits2016;9:84-7 PMCID:PMC5013857

[68] Santo L,Kung AL,Tamang D.Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma..Blood2012;119:2579-89 PMCID:PMC3337713

[69] Cosenza M,Marcheselli L,Pozzi S.Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine..Apoptosis2017;22:827-40 PMCID:PMC5401712

[70] Vogl DT,Jagannath S,Hari P.Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma..Clin Cancer Res2017;23:3307-15 PMCID:PMC5496796

[71] Minami J,Mazitschek R,Ghosh B.Histone deacetylase 3 as a novel therapeutic target in multiple myeloma..Leukemia2014;28:680-9 PMCID:PMC4165599

[72] Tang S,Zhe N,Xu J.Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway..Anticancer Drugs2018;29:61-74

[73] Harada T,Grondin Y,Sagawa M.HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications..Leukemia2017;31:2670-7 PMCID:PMC5681897

[74] Guerriero JL,Ponichtera HE,Pourzia AL.Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages..Nature2017;543:428-32

[75] Marek L,Hansen FK,Gohlke H.Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells..J Med Chem2013;56:427-36

[76] Li X,Kuang X,Li H.Histone deacetylase inhibitor LMK-235-mediated HO-1 expression induces apoptosis in multiple myeloma cells via the JNK/AP-1 signaling pathway..Life Sci2019;223:146-57

[77] Wanek J,Beyreis M,Helm K.Pharmacological inhibition of class IIA HDACs by LMK-235 in pancreatic neuroendocrine tumor cells..Int J Mol Sci2018;19:3128 PMCID:PMC6213165

[78] Gradilone SA,Bogert PS,Gajdos GB.HDAC6 inhibition restores ciliary expression and decreases tumor growth..Cancer Res2013;73:2259-70 PMCID:PMC3768151

[79] Woan KV,Perez-Villaroel P,Cheng F.Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: enhanced antitumor immunity and impaired cell proliferation..Mol Oncol2015;9:1447-57 PMCID:PMC4523430

[80] Wang F,Yi Y,Qiu Q.SKLB-23bb, A HDAC6-Selective inhibitor, exhibits superior and broad-spectrum antitumor activity via additionally targeting microtubules..Mol Cancer Ther2018;17:763-75

[81] Ma XJ,Li ZJ,Wu D.HDAC-selective inhibitor cay10603 has single anti-tumour effect in Burkitt’s lymphoma cells by impeding the cell cycle..Curr Med Sci2019;39:228-36

[82] Wang Z,Hu P,Gong J.HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma..Oncol Rep2016;36:589-97

[83] Bergman JA,Perez-Villarroel P,Sotomayor EM.Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth..J Med Chem2012;55:9891-9 PMCID:PMC3562128

[84] Wu H,Zhang Z,Li Z.Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity..J Med Chem2019;62:7042-57

[85] Sun X,Sun X,Li H.The selective HDAC6 inhibitor nexturastat A induces apoptosis, overcomes drug resistance and inhibits tumor growth in multiple myeloma..Biosci Rep2019;39:1-11 PMCID:PMC6430725

[86] Rettig I,Trippel F,Burhenne J.Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation..Cell Death Dis2015;6:1-14 PMCID:PMC4669789

[87] Balasubramanian S,Luo W,Verner E.A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas..Leukemia2008;22:1026-34

[88] Lopez G,Bid HK,Constantino D.HDAC8, a potential therapeutic target for the treatment of malignant peripheral nerve sheath tumors (MPNST)..PLoS One2015;10:1-12 PMCID:PMC4511720

[89] Wang R,Robinson V,Hessler P.Targeting lineage-specific MITF pathway in human melanoma cell lines by A-485, the selective small-molecule inhibitor of p300/CBP..Mol Cancer Ther2018;17:2543-50

[90] Lasko LM,Edalji RP,Montgomery D.Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours..Nature2017;550:128-32 PMCID:PMC6050590

[91] Bowers EM,Mukherjee C,Wang L.Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor..Chem Biol2010;17:471-82 PMCID:PMC2884008

[92] Dahlin JL,Strasser JM,Szewczyk MM.Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors..Nat Commun2017;8:1-14 PMCID:PMC5688144

[93] Wang R,Robinson V,Hessler P.Targeting Lineage-specific MITF pathway in human melanoma cell lines by A-485, the selective small-molecule inhibitor of p300/CBP..Mol Cancer Ther2018;17:2543-50

[94] Filippakopoulos P,Mangos M,Lambert JP.Histone recognition and large-scale structural analysis of the human bromodomain family..Cell2012;149:214-31 PMCID:PMC3326523

[95] Wai DCC,Campbell AE,Lorna EWW.The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators..J Biol Chem2018;293:7160-75

[96] Cochran AG,Sims RJ.Bromodomains: a new target class for drug development..Nat Rev Drug Discov2019;18:609-28

[97] Sahni JM.Targeting bromodomain and extraterminal proteins in breast cancer..Pharmacol Res2018;129:156-76 PMCID:PMC5828951

[98] Bechter O.Make your best BET: the emerging role of BET inhibitor treatment in malignant tumors..Pharmacol Ther2020;208:107479

[99] Faivre EJ,Albert DH,Plotnik JP.Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer..Nature2020;578:306-10

[100] Chen D,Yan Z,Zhou F.Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins..Eur J Med Chem2019;182:111633

[101] Rathore R,Varghese E,Büsselberg D.Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)..Apoptosis2017;22:898-919 PMCID:PMC5486846

[102] Von Karstedt S,Walczak H.Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy..Nat Rev Cancer2017;17:352-66

[103] Croft M.Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases..Nat Rev Rheumatol2017;13:217-33 PMCID:PMC5486401

[104] Liu X,Khuri FR.Decoy receptor 2 (<em>DcR2</em>) is a p53 target gene and regulates chemosensitivity..Cancer Res2005;65:9169-75

[105] Mansour NM,Wu L,Cahill KE.Decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide..Cancer Res2015;75:2039-48 PMCID:PMC4433625

[106] Liu X,Khuri FR.p53 upregulates death receptor 4 expression through an intronic p53 Binding site..Cancer Res2004;64:5078-83

[107] Shetty S,Brown JG,Vegh-Yarema N.Transcription factor NF-κB differentially regulates death receptor 5 expression involving histone deacetylase 1..Mol Cell Biol2005;25:5404-16 PMCID:PMC1156987

[108] Woo SM,Min KJ.BIX-01294 sensitizes renal cancer Caki cells to TRAIL-induced apoptosis through downregulation of survivin expression and upregulation of DR5 expression..Cell Death Discov2018;4:29 PMCID:PMC5841352

[109] Kim SY,Heo SH,Kwon TK.Inhibition of euchromatin histone-lysine N-methyltransferase 2 sensitizes breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through reactive oxygen species-mediated activating transcription factor 4-C/EBP homologous protein-de..Mol Carcinog2018;57:1492-506

[110] Benoit YD,Witherspoon MS,Gudas LJ.Inhibition of PRC2 histone methyltransferase activity increases TRAIL-mediated apoptosis sensitivity in human colon cancer cells..J Cell Physiol2013;228:764-72 PMCID:PMC3947628

[111] Kasman L,Voelkel-Johnson C.Histone deacetylase inhibitors restore cell surface expression of the coxsackie adenovirus receptor and enhance CMV promoter activity in castration-resistant prostate cancer cells..Prostate Cancer2012;2012:137163 PMCID:PMC3263646

[112] Srivastava RK,Shankar S.MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo..Mol Cancer Ther2010;9:3254-66

[113] Borbone E,De Bellis F,Chiappetta G.Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation..Oncogene2010;29:105-16

[114] Nebbioso A,Conte M,Ciro A.C-Myc modulation and acetylation is a key HDAC inhibitor target in cancer..Clin Cancer Res2017;23:2542-55

[115] Zhang B,Chen D,Haisma HJ.Histone deacetylase inhibitors sensitize TRAIL-induced apoptosis in colon cancer cells..Cancers (Basel)2019;11:645 PMCID:PMC6562715

[116] Kurt IC,Kaya E,Kazancioglu S.KDM2B, an H3K36-specific demethylase, regulates apoptotic response of GBM cells to TRAIL..Cell Death Dis2017;8:e2897 PMCID:PMC5520939

[117] Tanaka H,Oh-hara T,Naito M.PRMT5, a novel TRAIL receptor-binding protein, inhibits TRAIL-induced apoptosis via nuclear factor-κB activation..Mol Cancer Res2009;7:557-69

[118] Li M,Xu L,Su L.The arginine methyltransferase PRMT5 and PRMT1 distinctly regulate the degradation of anti-apoptotic protein CFLAR L in human lung cancer cells..J Exp Clin Cancer Res2019;38:1-13 PMCID:PMC6368745

[119] Kauh J,Xia M,Yang L.C-FLIP degradation mediates sensitization of pancreatic cancer cells to trail-induced apoptosis by the histone deacetylase inhibitor LBH589..PLoS One2010;5:e10376 PMCID:PMC2860986

[120] Symanowski J,Zawel L,Pass H.A histone deacetylase inhibitor LBH589 downregulates XIAP in mesothelioma cell lines which is likely responsible for increased apoptosis with TRAIL..J Thorac Oncol2009;4:149-60

[121] Kerr E,McLaughlin KM,Dolan S.Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis..Cell Death Differ2012;19:1317-27 PMCID:PMC3392639

[122] Klingbeil O,Gelato KA,Lejeune P.Inhibition of bet bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents..Cell Death Dis2016;7:1-13 PMCID:PMC5059870

[123] Zhao L,Hong EK,Wood GS.Preclinical studies support combined inhibition of BET family proteins and histone deacetylases as epigenetic therapy for cutaneous T-cell lymphoma..Neoplasia (United States)2019;21:82-92 PMCID:PMC6280696