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

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.