Oncogenic snoRNA SNORD78 fuels colorectal cancer by protecting m6A reader IMP2, enhancing phospholipid metabolism

Colorectal cancer (CRC) remains a highly lethal malignancy, with complex oncogenic signaling networks contributing to its progression. N6-methyladenosine (m6A) modification, a critical epitranscriptomic regulator, is implicated in tumor development, but the specific mechanisms by which small nucleolar RNAs (snoRNAs) regulate m6A modifications in CRC are not well understood. Understanding these interactions could reveal novel therapeutic targets, as current standard-of-care often faces challenges with resistance and systemic toxicity. This study addresses this gap by deciphering the precise interplay between a specific snoRNA, SNORD78, and the m6A reader IMP2 in CRC.

Researchers systematically investigated the interaction between SNORD78 and the m6A reader IMP2 in colorectal cancer (CRC) cells and organoids. They utilized an ASO-78 (SNORD78-targeting antisense oligonucleotide) to suppress SNORD78 activity and an IMP2-IN1 (IMP2 inhibitor) to block IMP2 function. The study examined CRC cell proliferation, endoplasmic reticulum stress (ERS) levels, and phosphatidylcholine (PC) content. Mechanistic studies involved identifying the specific binding elements on SNORD78 (the "UAAUGA" element in its C-D box region) and the ubiquitination site on IMP2 (Lys221) to understand how SNORD78 blocks TRIM25-mediated degradation of IMP2. They also analyzed m6A positions on target mRNAs PIK3CD (m6A-3208) and CHKA (m6A-1619) to understand their stability and translation.

The study revealed that oncogenic SNORD78 specifically stabilizes the m6A reader IMP2, thereby activating the PIK3CD-CHKA-Kennedy pathway in an m6A-dependent manner. This activation promotes endoplasmic reticulum stress (ERS) and phosphatidylcholine (PC) biosynthesis, which are key drivers of colorectal cancer (CRC) progression. Mechanistically, SNORD78, via its "UAAUGA" element, directly binds to the Lys221 ubiquitination site of IMP2, preventing TRIM25-mediated degradation and maintaining IMP2 stability. IMP2, in turn, enhanced the stability and translation of target mRNAs PIK3CD and CHKA by recognizing their specific m6A positions (m6A-3208 and m6A-1619), reshaping the phosphatidylcholine metabolite profile in CRC cells. The therapeutic potential was demonstrated with an antisense oligonucleotide:

ASO-78 significantly inhibited CRC cell proliferation, reduced ERS levels, and decreased phosphatidylcholine content. Furthermore, the combination of ASO-78 and IMP2-IN1 (an IMP2 inhibitor) synergistically exhibited an excellent proliferation-inhibiting effect in CRC organoids, suggesting a dual-blocking strategy for the SNORD78-IMP2 axis.