DERP6 (ELP5) and C3ORF75 (ELP6) Regulate Tumorigenicity and Migration of Melanoma Cells as Subunits of Elongator
DERP6 (ELP5) and C3ORF75 (ELP6) Regulate Tumorigenicity and Migration of Melanoma Cells as Subunits of Elongator
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DOI：
10.1074/jbc.m112.402727
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发表时间：
2012-09-21
影响因子：
4.8
通讯作者：
Chariot, Alain
中科院分区：
文献类型：
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作者：
Close, Pierre;Gillard, Magali;Chariot, Alain
Elongator 复合体由 6 个亚基 (Elp1-Elp6) 组成，通过细胞核中的组蛋白乙酰化以及细胞质中的 tRNA 修饰促进 RNAPII 转录物延伸。这种乙酰转移酶复合物直接或间接调节许多生物过程，从酵母的胞吐作用和对热休克的抵抗力到高等真核生物的细胞迁移和神经元分化。人类 ELP1 至 ELP4 的身份已被报道，但人类 ELP5 和 ELP6 仍未得到表征。在这里，我们报告 DERP6 (ELP5) 和 C3ORF75 (ELP6) 编码人类 Elongator 的这些亚基。我们通过生化分析和细胞测定的结合进一步研究了这两个亚基的重要性和功能。我们的结果表明，DERP6/ELP5 是 Elongator 完整性所必需的，并将 ELP3 直接连接到 ELP4。重要的是，通过 ELP1 或 ELP3 耗尽 Elongator 后，黑色素瘤来源的细胞的迁移和致瘤性显着降低。引人注目的是，DERP6/ELP5 和 C3ORF75/ELP6 耗尽的黑色素瘤细胞具有相似的缺陷，进一步支持了 DERP6/ELP5 和 C3ORF75/ELP6 对于伸长器功能至关重要的观点。总之，我们的数据确定 DERP6/ELP5 和 C3ORF75/ELP6 作为 Elongator 的组成亚基，是黑色素瘤细胞迁移、侵袭和致瘤性的关键参与者。
The Elongator complex is composed of 6 subunits (Elp1-Elp6) and promotes RNAPII transcript elongation through histone acetylation in the nucleus as well as tRNA modification in the cytoplasm. This acetyltransferase complex directly or indirectly regulates numerous biological processes ranging from exocytosis and resistance to heat shock in yeast to cell migration and neuronal differentiation in higher eukaryotes. The identity of human ELP1 through ELP4 has been reported but human ELP5 and ELP6 have remained uncharacterized. Here, we report that DERP6 (ELP5) and C3ORF75 (ELP6) encode these subunits of human Elongator. We further investigated the importance and function of these two subunits by a combination of biochemical analysis and cellular assays. Our results show that DERP6/ELP5 is required for the integrity of Elongator and directly connects ELP3 to ELP4. Importantly, the migration and tumorigenicity of melanoma-derived cells are significantly decreased upon Elongator depletion through ELP1 or ELP3. Strikingly, DERP6/ELP5 and C3ORF75/ELP6-depleted melanoma cells have similar defects, further supporting the idea that DERP6/ELP5 and C3ORF75/ELP6 are essential for Elongator function. Together, our data identify DERP6/ELP5 and C3ORF75/ELP6 as key players for migration, invasion and tumorigenicity of melanoma cells, as integral subunits of Elongator.