Affiliations
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
2Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.
3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
4Division of Pulmonary and Critical Care, Boston University, Boston, MA, 02118, USA.
5Department of Pathology, National University Health System, Singapore, Singapore.
6Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
7Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore.
8Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California, La Jolla, San Diego, USA.
9Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. yvonnetay@nus.edu.sg.
10Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore. yvonnetay@nus.edu.sg.
Abstract
In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we identify LARP1 as one of the most upregulated RBPs in colorectal cancer (CRC) and demonstrate its oncogenic properties. We perform LARP1:RNA interactome profiling and unveil a previously unexplored role for LARP1 in targeting the 3’UTR of oncogenes in CRC. Notably, we identify the proto-oncogenic transcription factor MYC as a key LARP1-regulated target. Our data show that LARP1 positively modulates MYC expression by associating with its 3’UTR. In addition, antisense oligonucleotide-mediated blocking of the interaction between LARP1 and the MYC 3’UTR reduces MYC expression and in vitro CRC growth. Furthermore, a systematic analysis of LARP1:protein interactions reveals IGF2BP3 and YBX1 as LARP1-interacting proteins that also regulate MYC expression and CRC development. Finally, we demonstrate that MYC reciprocally modulates LARP1 expression by targeting its enhancer. In summary, our data reveal a critical, previously uncharacterized role of LARP1 in promoting CRC tumorigenesis, validate its direct regulation of the proto-oncogene MYC and delineate a model of the positive feedback loop between MYC and LARP1 that promotes CRC growth and development.
Keywords: Cancer; LARP1; MYC; Post-transcriptional regulation; RNA-binding protein.