Targeted Epigenetic Interventions in Cancer with an Emphasis on Pediatric Malignancies

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2023 Jan 21

PMID 36671446

Authors

Zsuzsanna Gaal

Affiliations

Soon will be listed here.

Abstract

Over the past two decades, novel hallmarks of cancer have been described, including the altered epigenetic landscape of malignant diseases. In addition to the methylation and hyd-roxymethylation of DNA, numerous novel forms of histone modifications and nucleosome remodeling have been discovered, giving rise to a wide variety of targeted therapeutic interventions. DNA hypomethylating drugs, histone deacetylase inhibitors and agents targeting histone methylation machinery are of distinguished clinical significance. The major focus of this review is placed on targeted epigenetic interventions in the most common pediatric malignancies, including acute leukemias, brain and kidney tumors, neuroblastoma and soft tissue sarcomas. Upcoming novel challenges include specificity and potential undesirable side effects. Different epigenetic patterns of pediatric and adult cancers should be noted. Biological significance of epigenetic alterations highly depends on the tissue microenvironment and widespread interactions. An individualized treatment approach requires detailed genetic, epigenetic and metabolomic evaluation of cancer. Advances in molecular technologies and clinical translation may contribute to the development of novel pediatric anticancer treatment strategies, aiming for improved survival and better patient quality of life.

References

Huegel J, Dinh C, Martinelli M, Bracho O, Rosario R, Hardin H . CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells. Oncotarget. 2022; 13:890-904. PMC: 9295707. DOI: 10.18632/oncotarget.28254. View

Shinohara H, Sawado R, Nakagawa M, Hattori A, Yamagata K, Tauchi K . Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors. Mol Ther Oncolytics. 2022; 27:14-25. PMC: 9529991. DOI: 10.1016/j.omto.2022.09.006. View

Teng S, Ma C, Yu Y, Yi C . Hydroxyurea promotes TET1 expression and induces apoptosis in osteosarcoma cells. Biosci Rep. 2019; 39(5). PMC: 6522705. DOI: 10.1042/BSR20190456. View

Pan T, Qi J, You T, Yang L, Wu D, Han Y . Addition of histone deacetylase inhibitors does not improve prognosis in patients with myelodysplastic syndrome and acute myeloid leukemia compared with hypomethylating agents alone: A systematic review and meta-analysis of seven prospective cohort.... Leuk Res. 2018; 71:13-24. DOI: 10.1016/j.leukres.2018.06.007. View

Armas-Pineda C, Arenas-Huertero F, Perezpenia-Diazconti M, Chico-Ponce de Leon F, Sosa-Sainz G, Lezama P . Expression of PCAF, p300 and Gcn5 and more highly acetylated histone H4 in pediatric tumors. J Exp Clin Cancer Res. 2007; 26(2):269-76. View

Lin H, Chuang J, Wang P, Lin T, Wu M, Hsu W . 5-aza-2'-Deoxycytidine Induces a RIG-I-Related Innate Immune Response by Modulating Mitochondria Stress in Neuroblastoma. Cells. 2020; 9(9). PMC: 7564572. DOI: 10.3390/cells9091920. View

Bueno A, da Silva R, Stecchini M, Marrero-Gutierrez J, de Almeida E Silva D, Cardinalli I . DNA methylation is a comprehensive marker for pediatric adrenocortical tumors. Endocr Relat Cancer. 2022; 29(11):599-613. DOI: 10.1530/ERC-22-0145. View

Al-Ghabkari A, Narendran A . Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells . Cancer Biol Ther. 2021; 22(4):333-344. PMC: 8183514. DOI: 10.1080/15384047.2021.1902913. View

Wang T, Li X, Sun S . EX527, a Sirt-1 inhibitor, induces apoptosis in glioma via activating the p53 signaling pathway. Anticancer Drugs. 2019; 31(1):19-26. DOI: 10.1097/CAD.0000000000000824. View

10.

Chen I, Sethy B, Liou J . Recent Update of HDAC Inhibitors in Lymphoma. Front Cell Dev Biol. 2020; 8:576391. PMC: 7494784. DOI: 10.3389/fcell.2020.576391. View

11.

Fong J, Pignata L, Goy P, Kawabata K, Chun-Wei Lee S, Koh C . Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. Cancer Cell. 2019; 36(2):194-209.e9. PMC: 7194031. DOI: 10.1016/j.ccell.2019.07.003. View

12.

Zhou X, Li X, Liao L, Han J, Huang J, Li J . P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib. Acta Pharmacol Sin. 2021; 43(2):457-469. PMC: 8791947. DOI: 10.1038/s41401-021-00643-2. View

13.

Illiano M, Conte M, Salzillo A, Ragone A, Spina A, Nebbioso A . The KDM Inhibitor GSKJ4 Triggers CREB Downregulation via a Protein Kinase A and Proteasome-Dependent Mechanism in Human Acute Myeloid Leukemia Cells. Front Oncol. 2020; 10:799. PMC: 7289982. DOI: 10.3389/fonc.2020.00799. View

14.

Madrazo E, Ruano D, Abad L, Alonso-Gomez E, Sanchez-Valdepenas C, Gonzalez-Murillo A . G9a Correlates with VLA-4 Integrin and Influences the Migration of Childhood Acute Lymphoblastic Leukemia Cells. Cancers (Basel). 2018; 10(9). PMC: 6162492. DOI: 10.3390/cancers10090325. View

15.

Metais A, Bouchoucha Y, Kergrohen T, Dangouloff-Ros V, Maynadier X, Ajlil Y . Pediatric spinal pilocytic astrocytomas form a distinct epigenetic subclass from pilocytic astrocytomas of other locations and diffuse leptomeningeal glioneuronal tumours. Acta Neuropathol. 2022; 145(1):83-95. PMC: 9582396. DOI: 10.1007/s00401-022-02512-6. View

16.

Sun J, He X, Zhu Y, Ding Z, Dong H, Feng Y . SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function. Cell Stem Cell. 2018; 23(3):355-369.e9. PMC: 6143172. DOI: 10.1016/j.stem.2018.07.018. View

17.

Kohrogi K, Hino S, Sakamoto A, Anan K, Takase R, Araki H . LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα. Blood Adv. 2021; 5(9):2305-2318. PMC: 8114557. DOI: 10.1182/bloodadvances.2020003521. View

18.

Jin Y, Cao Q, Chen C, Du X, Jin B, Pan J . Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia (ALL) cells and eliminates ALL stem/progenitor cells. BMC Cancer. 2015; 15:226. PMC: 4394409. DOI: 10.1186/s12885-015-1282-1. View

19.

Janisiak J, Kopytko P, Tkacz M, Roginska D, Peruzynska M, Machalinski B . Protein Arginine Methyltransferase (PRMT) Inhibitors-AMI-1 and SAH Are Effective in Attenuating Rhabdomyosarcoma Growth and Proliferation in Cell Cultures. Int J Mol Sci. 2021; 22(15). PMC: 8348967. DOI: 10.3390/ijms22158023. View

20.

Shi H, Tao T, Abraham B, Durbin A, Zimmerman M, Kadoch C . ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression. Sci Adv. 2020; 6(29):eaaz3440. PMC: 7439613. DOI: 10.1126/sciadv.aaz3440. View