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

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 <i>SNORD78</i> and the m⁶A reader IMP2 in CRC. We demonstrate that <i>SNORD78</i> 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 <i>SNORD78</i>-targeting antisense oligonucleotide (ASO), ASO-78, effectively suppresses ERS and PC levels, inhibiting CRC progression. Mechanistically, <i>SNORD78</i>, 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 <i>PIK3CD</i> and <i>CHKA</i> 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 <i>SNORD78</i>-IMP2 axis, exhibits an excellent proliferation-inhibiting effect in CRC organoids. This study not only reveals a mechanism by which the <i>SNORD78</i>-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.