Oncogenic RAS Regulates Long Noncoding RNA Orilnc1 in Human Cancer

Dongmei Zhang, Gao Zhang, Xiaowen Hu, Lawrence Wu, Yi Feng, Sidan He, Youyou Zhang, Zhongyi Hu, Lu Yang, Tian Tian, Weiting Xu, Zhi Wei, Yiling Lu, Keith T Flaherty, Xiaomin Zhong, Gordon B Mills, Phyllis A Gimotty, Xiaowei Xu, Meenhard Herlyn, Lin Zhang

RAS and its downstream cascades transmit cellular signals resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long non-coding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA Orilnc1 as a genetic target of RAS that is critical for RAS oncogenicity. Orilnc1 expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1. Orilnc1 was highly expressed in BRAF-mutant cancers such as melanoma. Silencing of Orilnc1 blocked tumor cell proliferation and growth in vitro and in vivo. Additionally, Orilnc1 blockade reduced expression of Cyclin E1 and induced G1/S cell cycle arrest in tumor cells. Taken together, our results identify Orilnc1 as a novel, non-protein mediator of RAS/RAF activation which may serve as a therapeutic target in RAS/RAF-driven cancers.