Human Ccr4 and Caf1 Deadenylases Regulate Proliferation and Tumorigenicity of Human Gastric Cancer Cells via Modulating Cell Cycle Progression

Simple Summary Cancer cells generally reprogram their gene expression profiles to satisfy continuous growth, proliferation, and metastasis. Most eukaryotic mRNAs are degraded in a deadenylation-dependent pathway, in which deadenylases are the key enzymes. We found that human Ccr4 (hCcr4a/b) and Caf1 (hCaf1a/b), the dominant cytosolic deadenylases, were dysregulated in several types of cancers including stomach adenocarcinoma. Stably knocking down hCaf1a/b or hCcr4a/b blocks cell cycle progression by enhancing the levels of cell cycle inhibitors and by inhibiting the formation of processing bodies, which are cytosolic foci involved in mRNA metabolism. More importantly, depletion of hCaf1a/b or hCcr4a/b dramatically inhibits cell proliferation and tumorigenicity. Our results suggest that perturbating global RNA metabolism may provide a potential novel strategy for cancer treatment. Cancer cells generally have reprogrammed gene expression profiles to meet the requirements of survival, continuous division, and metastasis. An interesting question is whether the cancer cells will be affected by interfering their global RNA metabolism. In this research, we found that human Ccr4a/b (hCcr4a/b) and Caf1a/b (hCaf1a/b) deadenylases, the catalytic components of the Ccr4-Not complex, were dysregulated in several types of cancers including stomach adenocarcinoma. The impacts of the four deadenylases on cancer cell growth were studied by the establishment of four stable MKN28 cell lines with the knockdown of hCcr4a/b or hCaf1a/b or transient knockdown in several cell lines. Depletion of hCcr4a/b or hCaf1a/b significantly inhibited cell proliferation and tumorigenicity. Mechanistic studies indicated that the cells were arrested at the G2/M phase by knocking down hCaf1a, while arrested at the G0/G1 phase by depleting hCaf1b or hCcr4a/b. The four enzymes did not affect the levels of CDKs and cyclins but modulated the levels of CDK-cyclin inhibitors. We identified that hCcr4a/b, but not hCaf1a/b, targeted the p21 mRNA in the MKN28 cells. Furthermore, depletion of any one of the four deadenylases dramatically impaired processing-body formation in the MKN28 and HEK-293T cells. Our results highlight that perturbating global RNA metabolism may severely affect cancer cell proliferation, which provides a potential novel strategy for cancer treatment.

Automated summary

Cancer cells reprogram gene expression profiles to support continuous growth, proliferation, and metastasis. Dysregulation of the human deadenylases Ccr4a/b and Caf1a/b is observed in various types of cancers, and depletion of these enzymes inhibits cell proliferation and tumorigenicity. Targeting global RNA metabolism may offer a potential novel strategy for cancer treatment.