Ng Desi 1 2, Velda Teh 1, Qing Yun Tong 1, Chun You Lim 1, Hossein Tabatabaeian 1, Xiao Hong Chew 1, Avencia Sanchez-Mejias 1 3, Jia Jia Chan 1, Bin Zhang 1, Priyankaa Pitcheshwar 1, Bei-En Siew 4, Shi Wang 5, Kuok-Chung Lee 6, Choon-Seng Chong 4 6, Wai-Kit Cheong 6, Bettina Lieske 4 6, Ian Jse-Wei Tan 6, Ker-Kan Tan 4 6, Yvonne Tay 7 8
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, 117597, Singapore.
3Department of Experimental and Health Sciences, Pompeu Fabra University, 08003, Barcelona, Spain.
4Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
5Department of Pathology, National University Health System, Singapore, Singapore.
6Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore.
7Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. yvonnetay@nus.edu.sg.
8Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. yvonnetay@nus.edu.sg.
Abstract
3’UTR shortening in cancer has been shown to activate oncogenes, partly through the loss of microRNA-mediated repression. This suggests that many reported microRNA-oncogene target interactions may not be present in cancer cells. One of the most well-studied oncogenes is the transcription factor MYC, which is overexpressed in more than half of all cancers. MYC overexpression is not always accompanied by underlying genetic aberrations. In this study, we demonstrate that the MYC 3’UTR is shortened in colorectal cancer (CRC). Using unbiased computational and experimental approaches, we identify and validate microRNAs that target the MYC coding region. In particular, we show that miR-138 inhibits MYC expression and suppresses tumor growth of CRC and hepatocellular carcinoma (HCC) cell lines. Critically, the intravenous administration of miR-138 significantly impedes MYC-driven tumor growth in vivo. Taken together, our results highlight the previously uncharacterized shortening of the MYC 3’UTR in cancer, and identify miR-138 as a potent regulator of the heterogenous MYC transcript population.
© 2021. The Author(s).
