期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 46, 页码 17769-17779出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.003629
关键词
histone methylation; cell proliferation; post-translational modification (PTM); colon cancer; epigenetics; H4R3me2; protein acetylation; SIRT7; transmethylase; WDR77
资金
- National Natural Science Foundation of China [81270427, 81471405, 81671389, 81621063]
- National Research Program of China 973 Program [2013CB530801]
The histone transmethylase complex comprising WD repeat domain 77 (WDR77) and protein arginine methyltransferase 5 (PRMT5) catalyzes dimethylation of H4R3 (H4R3me2) and drives cancer cell proliferation and migration, but its regulation is not fully understood. Here, we report that sirtuin 7 (SIRT7) directly deacetylates WDR77 and that this deacetylation interferes with the WDR77-PRMT5 interaction and suppresses proliferation of human colon cancer HCT116 cells. Using co-expression in HEK293T cells and co-immunoprecipitation assays, we observed that SIRT7 deacetylates WDR77 at Lys-3 and Lys-243, which reduced of WDR77's interaction with PRMT5. More importantly, this reduction suppressed the transmethylase activity of the WDR77/PRMT5 complex, resulting in a reduction of the H4R3me2 modification. Rescue of the WDR77-KO HCT116 cells with a WDR77-2KR (K3R and K243R) variant yielded cell migration and proliferation rates that were significantly lower than those of WDR77-KO HCT116 cells rescued with WT WDR77. In summary, SIRT7 is a major deacetylase for WDR77, and SIRT7-mediated deacetylation of WDR77 at Lys-3 and Lys-243 weakens the WDR77-PRMT5 interaction and activity and thereby suppresses growth of cancer cells.
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