Global analysis of RNA-binding proteins identifies a positive feedback loop between LARP1 and MYC that promotes tumorigenesis

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 3; p. 147
• Main Authors: Desi, Ng, Tong, Qing Yun, Teh, Velda, Chan, Jia Jia, Zhang, Bin, Tabatabaeian, Hossein, Tan, Hui Qing, Kapeli, Katannya, Jin, Wenhao, Lim, Chun You, Kwok, Zhi Hao, Tan, Hwee Tong, Wang, Shi, Siew, Bei-En, Lee, Kuok-Chung, Chong, Choon-Seng, Tan, Ker-Kan, Yang, Henry, Kappei, Dennis, Yeo, Gene W., Chung, Maxey Ching Ming, Tay, Yvonne
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2022; Springer Nature B.V
• Subjects: 3' Untranslated Regions; Animals; Antisense oligonucleotides; Autoantigens - genetics; Autoantigens - metabolism; Binding; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogens; Cell Biology; Cell Proliferation - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Feedback; Feedback loops; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Gene regulation; HCT116 Cells; Humans; Life Sciences; Mice; Myc protein; Oncogenes; Original; Original Article; Positive feedback; Post-transcription; Protein interaction; Proteins; Proto-Oncogene Proteins c-myc - metabolism; Ribonucleic acid; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA; RNA-binding protein; SS-B Antigen; Transcriptome - genetics; Transfection; Tumor Burden - genetics; Tumorigenesis; Xenograft Model Antitumor Assays; Post-transcriptional regulation; RNA-binding protein; LARP1; MYC; Cancer
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-021-04093-1

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.