Given that colorectal cancer stem cells (CCSCs) play key roles in the tumor dormancy, metastasis and relapse, targeting CCSCs is a promising strategy in cancer therapy. Here, we aimed to identify new regulators of CCSCs and found that Cullin 4B (CUL4B), which possesses oncogenic properties in multiple solid tumors, drives the development and metastasis of colon cancer by sustaining cancer stem-like features. Elevated expression of CUL4B was confirmed in colon tumors and was associated with poor overall survival. Inhibition of CUL4B in cancer cell lines and patient-derived tumor organoids led to reduced sphere formation, proliferation and metastasis capacity. Mechanistically, CUL4B coordinates with PRC2 complex to repress miR34a expression,   thus up-regulates oncogenes including MYCN and NOTCH1, which are targeted by miR34a. Mutation of miR34a binding sites in the 3'UTR of the oncogenes rescues the phenotype caused by CUL4B depletion. Significant correlations were found between expression of CUL4B and miR34a (negatively), miR34a target genes (positively) in clinical samples from colon cancer patients. Collectively, our work demonstrates that CUL4B functions to repress miR34a in maintaining cancer stemness in CRC and provides a potential therapeutic target. SOURCE: Yanjun Li (201513616@mail.sdu.edu.cn) -  Shandong university

Pluto Bioinformatics

GSE143505: mRNA sequencing of human colorectal cancer organoids