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<p>Group 3 medulloblastoma (G3 MB) is an aggressive pediatric brain tumor with limited treatment options, necessitating the development of novel therapeutic strategies. The long noncoding RNA (lncRNA)&#xa0;<i>lnc-HLX-2-7</i>&#xa0;and its host-coding transcription factor,&#xa0;<i>HLX</i>, are highly expressed in G3 MB and act as oncogenic drivers. However, their role in regulating metabolism in G3 MB remains poorly understood. In this study, we investigate the metabolic functions of <i>lnc-HLX-2-7</i> in D425-Med and MED211 cells and uncover its role in regulating oxidative phosphorylation (OXPHOS) and ATP production through the TCA cycle. Our findings reveal that <i>lnc-HLX-2-7</i> is an upstream regulator of HLX, which, in turn, directly controls the expression of OXPHOS-related genes. Specifically, inhibition of <i>lnc-HLX-2-7</i> and HLX significantly reduces the expression of OXPHOS complexes I (<i>NDUFB8</i>), II (<i>SDHB</i>), and IV (<i>MTCO1</i>) by disrupting direct binding to and activating the promoters of these genes. Targeting oxidative phosphorylation with the small-molecule inhibitor IACS-010759 substantially inhibits G3 MB tumor progression in xenograft models, further supporting the critical role of OXPHOS in tumor progression. Rescue experiments demonstrate that overexpression of HLX in <i>lnc-HLX-2-7</i>-depleted cells restored OXPHOS gene expression and ATP production, confirming HLX as a downstream effector of <i>lnc-HLX-2-7</i>. These results highlight a coordinated <i>lnc-HLX-2-7</i>/HLX axis that regulates metabolism and oncogenesis in G3 MB. In conclusion, our findings establish <i>lnc-HLX-2-7</i> and its host-coding gene, <i>HLX</i>, as critical regulators of OXPHOS reprogramming and propose these molecules as promising therapeutic targets for this high-risk MB subtype.</p>

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LncRNA-HLX-2-7/HLX axis–dependent metabolic reprogramming drives cancer progression in group 3 medulloblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Keisuke Katsushima,
  • Yohei Sanada,
  • David A. Scott,
  • Stacie Stapleton,
  • George Jallo,
  • Charles G. Eberhart,
  • Ranjan J. Perera

摘要

Group 3 medulloblastoma (G3 MB) is an aggressive pediatric brain tumor with limited treatment options, necessitating the development of novel therapeutic strategies. The long noncoding RNA (lncRNA) lnc-HLX-2-7 and its host-coding transcription factor, HLX, are highly expressed in G3 MB and act as oncogenic drivers. However, their role in regulating metabolism in G3 MB remains poorly understood. In this study, we investigate the metabolic functions of lnc-HLX-2-7 in D425-Med and MED211 cells and uncover its role in regulating oxidative phosphorylation (OXPHOS) and ATP production through the TCA cycle. Our findings reveal that lnc-HLX-2-7 is an upstream regulator of HLX, which, in turn, directly controls the expression of OXPHOS-related genes. Specifically, inhibition of lnc-HLX-2-7 and HLX significantly reduces the expression of OXPHOS complexes I (NDUFB8), II (SDHB), and IV (MTCO1) by disrupting direct binding to and activating the promoters of these genes. Targeting oxidative phosphorylation with the small-molecule inhibitor IACS-010759 substantially inhibits G3 MB tumor progression in xenograft models, further supporting the critical role of OXPHOS in tumor progression. Rescue experiments demonstrate that overexpression of HLX in lnc-HLX-2-7-depleted cells restored OXPHOS gene expression and ATP production, confirming HLX as a downstream effector of lnc-HLX-2-7. These results highlight a coordinated lnc-HLX-2-7/HLX axis that regulates metabolism and oncogenesis in G3 MB. In conclusion, our findings establish lnc-HLX-2-7 and its host-coding gene, HLX, as critical regulators of OXPHOS reprogramming and propose these molecules as promising therapeutic targets for this high-risk MB subtype.