A Therapeutically Targetable Positive Feedback Loop Between nc-HLX-2-7, HLX, and MYC That Promotes Group 3 Medulloblastoma

Authors

Keisuke Katsushima
Kandarp Joshi
Menglang Yuan
Brigette Romero
Mona Batish
Stacie Stapleton
George Jallo
Elayaraja Kolanthai
Sudipta Seal
Olivier Saulnier
Michael D Taylor
Robert J Wechsler-Reya
Charles G Eberhart
Ranjan J Perera

Publication Date

3-26-2024

Journal

Cell Reports

DOI

10.1016/j.celrep.2024.113938

PMID

38460130

PMCID

PMC11372658

PubMedCentral® Posted Date

9-4-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Mice, Animals, Feedback, Medulloblastoma, Oncogenes, Cerebellar Neoplasms, RNA, Long Noncoding, Cell Proliferation, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Transcription Factors, Homeodomain Proteins

Abstract

Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.

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