The Long Non-coding RNA OTX2-AS1 Promotes Tumor Growth and Predicts Response to BCL-2 Inhibition in Medulloblastoma

Overview

Journal J Neurooncol

Publisher Springer

Date 2023 Nov 17

PMID 37976029

Authors

Nan Qin

Eunice Paisana

Daniel Picard

Gabriel Leprivier

Maike Langini

Carlos Custodia

Rita Cascao

Catleen Conrad

Mirko Peitzsch

Anja Stefanski

Kai Stuhler

Ute Fischer

Claudia C Faria

Sascha Dietrich

Guido Reifenberger

Marc Remke

Affiliations

Soon will be listed here.

Abstract

Purpose: Primary brain tumors are a leading cause of cancer-related death in children, and medulloblastoma is the most common malignant pediatric brain tumor. The current molecular characterization of medulloblastoma is mainly based on protein-coding genes, while little is known about the involvement of long non-coding RNAs (lncRNAs). This study aimed to elucidate the role of the lncRNA OTX2-AS1 in medulloblastoma.

Methods: Analyses of DNA copy number alterations, methylation profiles, and gene expression data were used to characterize molecular alterations of OTX2-AS1 in medulloblastoma tissue samples. In vitro analyses of medulloblastoma cell models and orthotopic in vivo experiments were carried out for functional characterization of OTX2-AS1. High-throughput drug screening was employed to identify pharmacological inhibitors, while proteomics and metabolomics analyses were performed to address potential mechanisms of drug action.

Results: We detected amplification and consecutive overexpression of OTX2 and OTX2-AS1 in a subset of medulloblastomas. In addition, OTX2-AS1 promoter methylation was linked to OTX2-AS1 expression. OTX2-AS1 knockout reduced medulloblastoma cell viability and cell migration in vitro and prolonged survival in the D283 orthotopic medulloblastoma mouse xenograft model. Pharmacological inhibition of BCL-2 suppressed the growth of OTX2-AS1 overexpressing medulloblastoma cells in vitro.

Conclusions: Our study revealed a pro-tumorigenic role of OTX2-AS1 in medulloblastoma and identified BCL-2 inhibition as a potential therapeutic approach to target OTX2-AS1 overexpressing medulloblastoma cells.

Citing Articles

Systematic transcriptomic analysis of childhood medulloblastoma identifies N6- methyladenosine-dependent lncRNA signatures associated with molecular subtype, immune cell inltration, and prognosis.

Joshi K, Yuan M, Katsushima K, Saulnier O, Ray A, Amankwah E Res Sq. 2024; .

PMID: 39281885 PMC: 11398580. DOI: 10.21203/rs.3.rs-4810070/v1.

Systematic transcriptomic analysis of childhood medulloblastoma identifies N6-methyladenosine-dependent lncRNA signatures associated with molecular subtype, immune cell infiltration, and prognosis.

Joshi K, Yuan M, Katsushima K, Saulnier O, Ray A, Amankwah E Acta Neuropathol Commun. 2024; 12(1):138.

PMID: 39198884 PMC: 11351195. DOI: 10.1186/s40478-024-01848-2.

A clinically compatible in vitro drug-screening platform identifies therapeutic vulnerabilities in primary cultures of brain metastases.

Jeising S, Nickel A, Trubel J, Felsberg J, Picard D, Leprivier G J Neurooncol. 2024; 169(3):613-623.

PMID: 38985431 PMC: 11341655. DOI: 10.1007/s11060-024-04763-7.

References

Fatica A, Bozzoni I . Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2013; 15(1):7-21. DOI: 10.1038/nrg3606. View

de Haas T, Oussoren E, Grajkowska W, Perek-Polnik M, Popovic M, Zadravec-Zaletel L . OTX1 and OTX2 expression correlates with the clinicopathologic classification of medulloblastomas. J Neuropathol Exp Neurol. 2006; 65(2):176-86. DOI: 10.1097/01.jnen.0000199576.70923.8a. View

Sigova A, Mullen A, Molinie B, Gupta S, Orlando D, Guenther M . Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proc Natl Acad Sci U S A. 2013; 110(8):2876-81. PMC: 3581948. DOI: 10.1073/pnas.1221904110. View

Hovestadt V, Remke M, Kool M, Pietsch T, Northcott P, Fischer R . Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 2013; 125(6):913-6. PMC: 3661908. DOI: 10.1007/s00401-013-1126-5. View

Varon M, Levy T, Mazor G, Ben David H, Marciano R, Krelin Y . The long noncoding RNA TP73-AS1 promotes tumorigenicity of medulloblastoma cells. Int J Cancer. 2019; 145(12):3402-3413. DOI: 10.1002/ijc.32400. View

Gao R, Zhang R, Zhang C, Liang Y, Tang W . LncRNA LOXL1-AS1 Promotes the Proliferation and Metastasis of Medulloblastoma by Activating the PI3K/AKT Pathway. Anal Cell Pathol (Amst). 2018; 2018:9275685. PMC: 6040304. DOI: 10.1155/2018/9275685. View

Schuller U, Schober F, Kretzschmar H, Herms J . Bcl-2 expression inversely correlates with tumour cell differentiation in medulloblastoma. Neuropathol Appl Neurobiol. 2004; 30(5):513-21. DOI: 10.1111/j.1365-2990.2004.00553.x. View

Adamson D, Shi Q, Wortham M, Northcott P, Di C, Duncan C . OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res. 2009; 70(1):181-91. PMC: 2943736. DOI: 10.1158/0008-5472.CAN-09-2331. View

Batista P, Chang H . Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013; 152(6):1298-307. PMC: 3651923. DOI: 10.1016/j.cell.2013.02.012. View

10.

Iyer M, Niknafs Y, Malik R, Singhal U, Sahu A, Hosono Y . The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015; 47(3):199-208. PMC: 4417758. DOI: 10.1038/ng.3192. View

11.

Peng K, Vasudevan H, Lockney D, Baum R, Hendrickson R, Raleigh D . Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance. Proc Natl Acad Sci U S A. 2022; 119(37):e2203738119. PMC: 9478675. DOI: 10.1073/pnas.2203738119. View

12.

Hwang J, Kuruvilla J, Mendelson D, Pishvaian M, Deeken J, Siu L . Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010; 16(15):4038-45. PMC: 3703245. DOI: 10.1158/1078-0432.CCR-10-0822. View

13.

Cavalli F, Remke M, Rampasek L, Peacock J, Shih D, Luu B . Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell. 2017; 31(6):737-754.e6. PMC: 6163053. DOI: 10.1016/j.ccell.2017.05.005. View

14.

Geisler S, Coller J . RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol. 2013; 14(11):699-712. PMC: 4852478. DOI: 10.1038/nrm3679. View

15.

Levesley J, Lusher M, Lindsey J, Clifford S, Grundy R, Coyle B . RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines. Neuro Oncol. 2011; 13(12):1265-76. PMC: 3223089. DOI: 10.1093/neuonc/nor129. View

16.

Di C, Liao S, Adamson D, Parrett T, Broderick D, Shi Q . Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res. 2005; 65(3):919-24. View

17.

Zhang Y, Wang T, Wang S, Xiong Y, Zhang R, Zhang X . Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma. Cancer Res. 2017; 78(4):962-973. DOI: 10.1158/0008-5472.CAN-17-1631. View

18.

Ellison D, Kocak M, Dalton J, Megahed H, Lusher M, Ryan S . Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol. 2010; 29(11):1400-7. PMC: 3525837. DOI: 10.1200/JCO.2010.30.2810. View

19.

Song H, Han L, Gao Q, Sun Y . Long non-coding RNA CRNDE promotes tumor growth in medulloblastoma. Eur Rev Med Pharmacol Sci. 2016; 20(12):2588-97. View

20.

Thakore P, DIppolito A, Song L, Safi A, Shivakumar N, Kabadi A . Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods. 2015; 12(12):1143-9. PMC: 4666778. DOI: 10.1038/nmeth.3630. View