Oncogenic snoRNA SNORD78 fuels colorectal cancer by protecting the m⁶A reader IMP2 to enhance phospholipid metabolism.

Authors

Yingqi Zhao, Xiaoyun Hu, Yalun Li, Jing Zhang, Hao Guo, Yuying Zhang, Ting Wu, Jinyu Guo, Yi Peng, Ying Che, Xianglong Zhu, Qiuchen Chen, David Grieve, Minjie Wei, Huizhe Wu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 29. Pages e2531283123. Jul 21, 2026. Epub Jul 14, 2026.

Abstract

Small nucleolar RNAs (snoRNAs) play crucial regulatory roles in various cancers. However, the mechanisms by which snoRNAs regulate N6-methyladenosine (m⁶A) modifications in colorectal cancer (CRC) remain unclear. This study systematically deciphered the precise interaction mechanism between SNORD78 and the m⁶A reader IMP2 in CRC. We demonstrate that SNORD78 specifically stabilizes IMP2 to activate the PIK3CD-CHKA-Kennedy pathway in an m⁶A-dependent manner, promoting endoplasmic reticulum stress (ERS) and phosphatidylcholine (PC) biosynthesis, thereby driving CRC. Conversely, the SNORD78-targeting antisense oligonucleotide (ASO), ASO-78, effectively suppresses ERS and PC levels, inhibiting CRC progression. Mechanistically, SNORD78, relying on the "UAAUGA" element in its C-D box region, specifically binds to the Lys221 ubiquitination site of IMP2, blocking TRIM25-mediated degradation of IMP2 and maintaining its stability. IMP2 enhanced the stability and translation of the target mRNAs PIK3CD and CHKA by recognizing their corresponding m⁶A positions, m⁶A-3208 and m⁶A-1619, respectively, to reshape the phosphatidylcholine metabolite profile in CRC cells. In terms of potential therapeutic strategies, the ASO-78 can significantly inhibit CRC cell proliferation, reduce ERS levels, and decrease phosphatidylcholine content. The combination of ASO-78 and IMP2 inhibitor IMP2-IN1, by dual blocking of the SNORD78-IMP2 axis, exhibits an excellent proliferation-inhibiting effect in CRC organoids. This study not only reveals a mechanism by which the SNORD78-IMP2 interaction regulates CRC occurrence and development but also provides theoretical basis for innovative therapeutic strategies for precise targeting of tumor snoRNA-m⁶A reader interactions.

PMID:
42446981
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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