SMYD3調控H2A.Z甲基化促進細胞周期與細胞增生

Abstract

甲基酶SMYD3在一般細胞中幾乎偵測不到，然而在數種癌細胞中卻有著高度的表現。目前對於SMYD3和癌細胞惡化的關係與其機制沒有全然的了解。在此我發現了一個新的SMYD3的受質H2A.Z。實驗指出SMYD3可藉由在H2A.Z的第101個胺基酸(離胺酸)上甲基化來增加H2A.Z及含有H2A.Z的核小體的穩定度。H2A.Z藉由甲基化防止和其伴護蛋白ANP32E結合，避免自核小體中被移除，同時增加和組蛋白H3的結合能力。此外，藉由微陣列基因晶片表現分析指出cyclin A1受SMYD3和H2A.ZK101me2調控。SMYD3和H2A.ZK101me2共同坐落於cyclin A1的啟動子區，活化期其表現並促進細胞週期G1/S的進程。在動物實驗中，於H2A.ZK101點突變的細胞中額外表現了cyclin A1亦可以促使癌細胞生長成腫瘤的能力。綜合以上我的發現，推測SMYD3所引起的H2A.ZK101me2可促進cyclin A1的表現，並促進乳癌細胞的增生。

The methyltransferase SMYD3 is nearly undetectable in normal human tissues but highly expressed in several cancers. The underlying mechanism by which SMYD3 is associated with tumor malignancy is not completely understood. Here, we demonstrate that histone H2A.Z is a novel substrate of SMYD3. SMYD3-mediated dimethylation of H2A.Z at lysine 101 (H2A.ZK101me2) could increase the stability of H2A.Z and the H2A.Z-containing nucleosomes by preventing its binding to the removal chaperon ANP32E and facilitate H2A.Z interaction with histone H3. Moreover, using microarray analysis, cyclin A1 was identified and its expression was co-regulated by SMYD3 and H2A.ZK101me2. The co-localization of SMYD3 and H2A.ZK101me2 was found at the promoter of cyclin A1 to up-regulate the gene expression and to promote G1/S progression. Consistently, exogenous expression of cyclin A1 in cells containing H2A.ZK101 mutants rescued tumor formation in a mouse model. Together our findings suggest that SMYD3-mediated H2A.ZK101 dimethylation activates cyclin A1 expression and contributes to breast cancer cell proliferation.