High fructose promotes MYCN-amplified neuroblastoma progression through NgBR-ACSS2-mediated biosynthesis of acetyl-CoA
Summary: MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725007181 |
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| Summary: | Summary: MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal role of acyl-coenzyme A (acyl-CoA) synthetase short-chain family member 2 (ACSS2), found to be heightened in MYCN-amplified neuroblastoma. We demonstrated that ACSS2 enhanced MYCN gene transcription and growth of MYCN-amplified neuroblastoma. Our results revealed a new mechanism wherein ACSS2 orchestrates MYCN transcription by escalating acetyl-CoA levels and histone acetylation, hinting at a metabolic participation in forcibly dictating MYCN regulation. We further demonstrated that fructose or acetate exacerbated neuroblastoma growth, which can be halted by the ACSS2 inhibitor. We further identified the Nogo-B receptor (NgBR) as the trigger for ACSS2 induction through the Akt-SREBP-1 pathway. Our findings propose NgBR as a novel therapeutic target, emphasizing the promising potential of metabolic therapies for managing aggressive MYCN-amplified neuroblastoma. |
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| ISSN: | 2211-1247 |