Abstract lncRNA-HLX-2-7 Amplifies the Host Gene, Transcription Factor HLX, and also MYC to Orchestrate Epigenetic–Metabolic Programs Driving Group 3 Medulloblastoma Group 3 medulloblastoma (G3 MB) is a highly aggressive pediatric brain tumor with poor outcomes and limited treatment options. We identify the long noncoding RNA lnc-HLX-2-7 and its host gene, the transcription factor HLX, as key regulators of tumor progression. lnc-HLX-2-7 functions upstream of HLX to promote oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle–dependent ATP production and epigenetic remodeling. Silencing lnc-HLX-2-7 or HLX reduces OXPHOS complexes I, II, and IV, impairs mitochondrial respiration, and decreases α-ketoglutarate, a key epigenetic regulator, which lowers tumor growth. Pharmacological inhibition of OXPHOS similarly slows G3 MB progression both in vitro and in vivo. Notably, overexpression of HLX restores OXPHOS activity and tumorigenic capacity in cells depleted for lnc-HLX-2-7, confirming HLX as a downstream mediator. These findings establish the lnc-HLX-2-7/HLX/MYC axis as a key driver of metabolic and epigenetic reprogramming in G3 MB, highlighting the RNA-dependent regulation of the transcriptional machinery. We have developed liposome-mediated nanosystems that carry siHLX, siMYC, and cisplatin as therapeutics for G3 MBs. Drugs were delivered to the brain via MRI-guided focused ultrasound. We will report here that both molecules (coding and noncoding) are promising targets for therapy in this high-risk medulloblastoma subtype.
Ranjan Perera (Tue,) studied this question.