Abstract 4504: MILIP is a pan cancer-associated long noncoding RNA that links MYC to inactivation of p53
Authors: Yuchen Feng, Liu Teng, Simonne K. Sherwin, Xiaoying Liu, Jinming Li, Margaret Farrelly, Yongyan Wu, Wei Gao, Zhuanyun Du, Yanfeng Xi, Jin Liang, Ting La, Yuanyuan Zhang, Hessam Tabatabaee, Xu Guang Yan, Hamed Yari, Tao Liu, Rick F. Thorne, Su Tang Guo, Binquan Wang, Xu Dong Zhang, Lei Jin
Journal: Cancer Research (2019)

Abstract The involvement of noncoding RNAs (ncRNAs) in cancer pathogenesis has been increasingly appreciated. Although the expression and function of ncRNAs is highly tissue type- and context-dependent, we have found that long ncRNA (lncRNA) MILIP (Myc-inducible lncRNA inactivating p53) is commonly upregulated in TCGA cancer samples across 20 cancer types and that its high expression was associated with poor overall survival of patients. The increase in MILIP expression was subsequently corroborated using in situ hybridization (ISH) in a panel of colorectal cancer and a cohort of non-small cell lung carcinoma samples compared with paired normal tissues and its negative relation to patient survival was confirmed. shRNA silencing of MILIP reduced viability and clonogenicity in various types of malignant cells including A549 lung cancer, MCF-7 and MDA-MB-231 breast cancer, HCT116 colon cancer, U2OS and Saos-2 osteosarcoma and BE(2)C neuroblastoma cells, and retarded A549 and MCF-7 xenograft growth. The inhibitory effect of MILIP silencing on cell viability was reversed by co-introduction of a shRNA-resistant mutant of MILIP, and moreover, introduction of exogenous MILIP promoted cell proliferation. Thus, MILIP functions as an oncogenic driver in diverse types of cancers. Strikingly, transcriptomics analysis revealed that the p53 pathway was mostly enriched in cells with MILIP silenced. Further mechanistic investigations demonstrated that MILIP was located to both the cytoplasm and nucleus, and that both fractions of MILIP contributed to its oncogenic role, as cytoplasmic MILIP accelerated p53 polyubiquitination and proteasomal degradation, whereas nuclear MILIP regulated p53 occupancy of its target promoters. Interestingly, we identified a consensus c-Myc binding site at the proximal promoter of the gene encoding MILIP that was transcriptionally activated upon binding to c-Myc. Indeed, MILIP upregulation appeared to be associated with MYC gene amplification. These results suggest that lncRNA MILIP plays a role in relaying oncogenic signaling of MYC to disabling the tumor suppressor p53. Of note, MILIP silencing also reduced viability of p53-null cancer cells and those carrying mutant p53, indicating that MILIP can also promote cancer pathogenesis independently of its effects on p53. Collectively, these findings identify MILIP as a pan-cancer associated oncogenic driver and implicate that MILIP may constitute a target for treatment of diverse types of cancer. Citation Format: Yuchen Feng, Liu Teng, Simonne K. Sherwin, Xiaoying Liu, Jinming Li, Margaret Farrelly, Yongyan Wu, Wei Gao, Zhuanyun Du, Yanfeng Xi, Jin Liang, Ting La, Yuanyuan Zhang, Hessam Tabatabaee, Xu Guang Yan, Hamed Yari, Tao Liu, Rick F. Thorne, Su Tang Guo, Binquan Wang, Xu Dong Zhang, Lei Jin. MILIP is a pan cancer-associated long noncoding RNA that links MYC to inactivation of p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4504.