Oncogenic SNORD12B activates the AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma via nucleus partitioning of PP-1α

Esophageal cancer is a complex malignancy and the sixth leading cause of cancer death worldwide. In Eastern Asia including China, about 90% of all incident cases have esophageal squamous cell carcinoma (ESCC). Mounting evidence elucidates that aberrant expression of various non-coding RNAs (ncRNAs) contributes to ESCC progression, but it remains unclear how small nucleolar RNAs (snoRNAs) are involved in ESCC development. We systemically screened clinically relevant snoRNAs in ESCC via integrative analyses of The Cancer Genome Atlas (TCGA) data and validation in ESCC tissues. We found that snoRNA SNORD12B was one of the most evidently upregulated snoRNAs in ESCC specimens and its high expression was significantly associated with poor prognosis of patients. SNORD12B profoundly promoted proliferation, migration, invasion, and metastasis of ESCC cells in vitro and in vivo, indicating its oncogene nature. In particular, SNORD12B could interact with PP-1 alpha, one of the three catalytic subunits of serine/threonine protein phosphatase 1, which is a major phosphatase that directly dephosphorylates AKT to suppress its activation. Interestingly, high levels of SNORD12B in ESCC cells could break interactions between 14-3-3 zeta and PP-1 alpha, abolish the retention of PP-1 alpha in the cytosol by 14-3-3 zeta and relocate PP-1 alpha from the cytosol to the nucleus. This led to sequestered PP-1 alpha in the nucleus, enhanced phosphorylation of AKT in the cytosol, activated AKT-mTOR-4EBP1 signaling, and, thus, ESCC progression. These insights would improve our understanding of how snoRNAs contribute to tumorigenesis and highlight the potential of snoRNAs as future therapeutic targets against cancers.

Automated summary

Research has shown that high expression of clinically relevant snoRNA SNORD12B in ESCC patients is associated with poor prognosis. SNORD12B interacts with PP-1α, disrupting the interaction between 14-3-3ζ and PP-1α, thus promoting the development of ESCC.