AbstractMammalian genomes encode large number of long noncoding RNAs (lncRNAs) that play key roles in various biological processes, including proliferation, differentiation, and stem cell pluripotency. Recent studies have addressed that some lncRNAs are dysregulated in human cancers and may play crucial roles in tumor development and progression. Here, we show that the lncRNAZNNT1is required for the proliferation and tumorigenicity of colon cancer cells with wild-type p53.ZNNT1knockdown leads to decreased ubiquitination and stabilization of p53 protein. Moreover, we demonstrate thatZNNT1needs to interact with SART3 to destabilize p53 and to promote the proliferation and tumorigenicity of colon cancer cells. We further show that SART3 is associated with the ubiquitin-specific peptidase USP15 and thatZNNT1may induce p53 destabilization by inhibiting this interaction. These results suggest thatZNNT1interferes with the SART3-USP15 complex-mediated stabilization of p53 protein and thereby plays important roles in the proliferation and tumorigenicity of colon cancer cells. Our findings suggest thatZNNT1may be a promising molecular target for the therapy of colon cancer.