Dr. Perera is director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital, a senior scientist in the Cancer & Blood Disorders Institute and an associate professor of oncology in the Johns Hopkins University School of Medicine. He also has a secondary affiliation with the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research.
Therapeutic Potential of Long noncoding RNA lnc-HLX-2-7 in Group III Medulloblastoma in Children
Keisuke Katsushima1,2, Bongyong Lee1,2, Robert J. Wechsler-Reya3, George Jallo2, Eric Raabe 1,4, Charles G. Eberhart1,4 and Ranjan J. Perera1,4
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231
2Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701
3 Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037
4 Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave – Ross Bldg 558, Baltimore, MD 21205
Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, particularly long noncoding RNAs (lncRNAs), contributes to MB sub-grouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in group 3 MBs. lnc-HLX-2-7 is highly upregulated in group 3 MB cell lines, patient-derived xenografts, and primary MBs compared to other MB sub-groups as assessed by qRT-PCR, RNA-seq, and RNA fluorescence in situ hybridization (FISH). Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. lnc-HLX-2-7-deleted cells injected into mouse cerebella produced smaller tumors than those derived from parental cells. This 517 bp intronic lncRNA lnc-HLX-2-7 is encoded within the HLX (H2.0-like homeobox) gene, a transcription factor with oncogenic function in blood cancers, but nothing is known thus far for any forms of MBs. We identified that lnc-HLX-2-7, accumulates in the promoter region and activates HLX expression by recruiting surrounding enhancer elements. The combined analysis of RNA-seq and ChIP-seq revealed that HLX directly binds to the promoters of many tumor-promoting genes, including MYC, and activates their expression. Antisense oligonucleotides targeting lnc-HLX-2-7 coated with cerium-oxide nanoparticles (CNP-lnc-HLX-2-7) efficiently represses tumor growth in the intracranial MB xenograft mouse model. In addition, we found that the combined treatment of CNP-lnc-HLX-2-7 with cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared to CNP-lnc-HLX-2-7 treatment. Our results highlight the importance of the lnc-HLX-2-7-HLX-MYC axis in regulating group 3 MB and provide a strong rationale for targeting lnc-HLX-2-7 as a potential RNA therapeutic for group 3 MBs.