Sirtuin 7–mediated deacetylation of WD repeat domain 77 (WDR77) suppresses cancer cell growth by reducing WDR77/PRMT5 transmethylase complex activity

Abstract

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.

SIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle

“…SIRT7 seems to have a dual role in cancer cells by targeting substrates (e.g., H3K18ac, ATM, and SMAD4). In this study, our data add a supportive evidence for the antineoplastic function of SIRT7 [59,60]. Namely, upon glucose deprivation, phosphorylated and activated SIRT7 is released from nucleoli into the nucleoplasm and then deacetylates PCAF, which serves as a major mechanism to control MDM2 degradation and p53 activation, resulting in cell proliferation arrest and cell death.…”

PRMT5 function and targeting in cancer

“…For example, MEP50/WDR77 phosphorylation by CDK4 increases PRMT5 activity via an undefined mechanism [67]. MEP50/WDR77 is deacetylated by SIRT7 in HCT116 cells, which interfere with PRMT5/WDR77 interaction and repress PRMT5 activity [120]. Whether the impaired SIRT7/WDR77 activity and HCT116 growth are PRMT5 dependent, remains to be established.…”

The current progress of histone deacetylase SIRT7

“…H3K36的去乙酰化有助于rDNA(ribosomal DNA)异染 色质沉默和基因组稳定性、转录延伸或DNA损伤修 复 [9,10] . 此外, SIRT7的非组蛋白去乙酰化底物包括 p53 [11] , PAF53 [12] , U3-55k [13] , GABPβ1 [14] , NPM1 [15] , PGK1 [16] , CDK9 [17] , DDB1 [18,19] , FKBP51 [20] , FOXO3 [21] , SMAD4 [22] , DDX21 [23] , WDR77 [24] , Fibrillarin [25] , ATM [26] 和Ran [27] 等.…”

“…但是其E3泛素连接酶至今没有确定. 最近, Yan等人 [41] 发现, SIRT7在精氨酸甲基转移酶PRMT6的 表 2 SIRT7催化底物及相关生物学功能 [7] p53 去乙酰化 抵抗细胞凋亡 [11] PAF53 去乙酰化 前体核糖RNA的合成和成熟 [12] U3-55k 去乙酰化 前体核糖RNA的合成和成熟 [13] GABPβ1 去乙酰化 线粒体功能 [14] NPM1 去乙酰化 衰老 [15] PGK1 去乙酰化 糖酵解 [16] FKBP51 去乙酰化 乳腺癌细胞中的AKT失活和化疗敏感性增加 [20] CDK9 去乙酰化 转录延伸 [17] FOXO3 去乙酰化 阻止LPS刺激时发生的细胞凋亡 [21] DDB1 去乙酰化 调节DDB1-CUL4的相互作用和CRL4活性 [18,19] SMAD4 去乙酰化 抑制乳腺癌肺转移 [22] DDX21 去乙酰化 基因组稳定性 [23] FBL 去乙酰化 rRNA合成 [25] H3K36 去乙酰化 rDNA异染色质沉默和基因组稳定性、转录延伸或DNA的损伤修复 [10] H3K37 去乙酰化 未知 [10] RanK37 去乙酰化 抑制p65向核外转移 [27] ATM 去乙酰化 DNA损伤修复 [26] WDR77 去乙酰化 抑制癌细胞生长 [24] OSX 去丙酰化 促进骨形成 [30] H3K36/K37 去丁酰化 未知 [10] H3K122 去琥珀酰化 DNA修复过程中的染色质重塑 [29] H4K91 去戊二酰化 调控染色质凝聚 [33] 催化下发生388位精氨酸甲基化, 抑制SIRT7的H3K18 去乙酰化酶活性, 从而调控葡萄糖传感和线粒体生物 发生. 此外, SIRT7的酶活性还受到染色质组成性DNA…”