Inflammation‐dependent overexpression of c‐Myc enhances CRL4DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis‐associated cancer

• Published in: The Journal of pathology Vol. 248; no. 4; pp. 464 - 475
• Main Authors: Liu, Hong, Lu, Wenzhu, He, Hongbo, Wu, Jin, Zhang, Caiguo, Gong, Hanlin, Yang, Chunmei
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2019; Wiley Subscription Services, Inc
• Subjects: Accumulation; Adenocarcinoma; Cell proliferation; Colitis; colitis‐associated cancer; Colon; Colorectal cancer; CUL4A; CUL4B; Cullin; Cytokines; c‐Myc; DCAF4; DNA damage; Epithelial cells; Inflammation; Inflammatory bowel disease; Myc protein; ST7; Tumor necrosis factor; Tumorigenesis; Tumorigenicity; Tumors; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5273

Inflammation is well known as an important driver of the initiation of colitis‐associated cancer (CAC). Some cytokines, such as IL‐6 and TNF‐α can activate expression of the oncogene c‐Myc (MYC) and regulate its downstream effects. Cullin‐RING E3 Ligases (CRLs) are emerging as master regulators controlling tumorigenesis. Here, we demonstrate that two cullin genes, CUL4A and CUL4B, but not other members, are specifically overexpressed in CAC tumour samples and positively correlate with levels of the proinflammatory cytokines IL‐1β and IL‐6. In vitro experiments revealed that the transcription factor c‐Myc can specifically activate the expression of CUL4A and CUL4B by binding to a conserved site (CACGTG) located in their promoters. Additionally, we found that both CUL4A and CUL4B can form an E3 complex with DNA damage‐binding protein 1 (DDB1) and DDB1‐CUL4‐associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). Overexpression of c‐Myc in human colon epithelial cells resulted in the accumulation of CUL4A, CUL4B and DCAF4, but degradation of ST7. In contrast, knockdown of c‐Myc, CUL4A or CUL4B in the colon adenocarcinoma cell line HT29 caused accumulation of ST7 and inhibition of cell proliferation, colony formation ability and in vivo tumour growth. Collectively, our results provide in vitro and in vivo evidence that c‐Myc regulates CRL4DCAF4 E3 ligase activity to mediate ubiquitination of ST7, whose presence is physiologically essential for CAC tumorigenesis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.