Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression
Jessica Silva-Fisher, Ha X. Dang, Nicole M. White, Matthew S. Strand, Bradley A. Krasnick, Emily B. Rozycki, Gejae Jeffers, Julie Grossman, Maureen Highkin, Cynthia Y. Tang, Christopher R. Cabanski, Abdallah M. Eteleeb, Jacqueline L. Mudd, S. Peter Goedegebuure, Jingqin Luo, Elaine R. Mardis, Richard K. Wilson, Timothy J. Ley, A. Craig Lockhart, Ryan C. Fields, Christopher A. Maher
Abstract
Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.