Ribosome Assembly Factor URB1 Contributes to Colorectal Cancer Proliferation via Transcriptional Activation of ATF4

Colorectal Cancer
05/09/2020

Cancer Sci. 2020 Sep 5. doi: 10.1111/cas.14643. Online ahead of print.

ABSTRACT

Ribosome assembly factor URB1 is essential for ribosome biogenesis. However, its latent role in cancer remains unclear. Cancer Genome Atlas database analysis and clinical tissue microarray staining showed that URB1 expression was upregulated in colorectal cancer (CRC) and prominently related to clinicopathological characteristics. URB1 silencing hampered human CRC cell proliferation and growth in vitro and in vivo. Microarray screening, ingenuity pathway analysis, and JASPAR assessment indicated


that activating transcription factor 4 (ATF4) and X-box binding protein 1 (XBP1) are potential downstream targets of URB1 and may transcriptionally interact through direct binding. URB1 silencing significantly decreased ATF4 and cyclin A2 (CCNA2) expression in vivo and in vitro. Restoration of ATF4 effectively reversed the malignant proliferation phenotype of URB1-silenced CRC cells. Dual-luciferase reporter and chromatin immunoprecipitation (CHIP) assays demonstrated that XBP1 transcriptionally activated ATF4 by binding with its promoter region. XBP1 co-localized with ATF4 in the nuclei of RKO cells, and ATF4 mRNA expression was positively regulated by XBP1. This study demonstrates that URB1 contributes to oncogenesis and CRC growth through XBP1-medaited transcriptional activation of ATF4. Therefore, URB1 may be a potential therapeutic target for CRC.