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首页> 外文期刊>Molecular and Cellular Biology >Chromatin Loading of E2F-MLL Complex by Cancer-Associated Coregulator ANCCA via Reading a Specific Histone Mark
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Chromatin Loading of E2F-MLL Complex by Cancer-Associated Coregulator ANCCA via Reading a Specific Histone Mark

机译：通过阅读特定的组蛋白标记，与癌症相关的调节器ANCCA对E2F-MLL复合物的染色质负载

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Histone modifications are regarded as the carrier of epigenetic memory through cell divisions. How the marks facilitate cell cycle-dependent gene expression is poorly understood. The evolutionarily conserved AAA ATPase ANCCA (AAA nuclear coregulator cancer-associated protein)/ATAD2 was identified as a direct target of oncogene AIB1/ACTR/SRC-3 and a transcriptional coregulator for estrogen and androgen receptors and is strongly implicated in tumorigenesis. We report here that ANCCA directly interacts with E2F1 to E2F3 and that its N terminus interacts with both the N and C termini of E2F1. ANCCA preferentially associates via its bromodomain with H3 acetylated at lysine 14 (H3K14ac) and is required for key cell cycle gene expression and cancer cell proliferation. ANCCA associates with chromosomes at late mitosis, and its occupancy at E2F targets peaks at the G1-to-S transition. Strikingly, ANCCA is required for recruitment of specific E2Fs to their targets and chromatin assembly of the host cell factor 1 (HCF-1)-MLL histone methyltransferase complex. ANCCA depletion results in a marked decrease of the gene activation-linked H3K4me3 mark. Bromodomain mutations disable ANCCA function as an E2F coactivator and its ability to promote cancer cell proliferation, while ANCCA overexpression in tumors correlates with tumor growth. Together, these results suggest that ANCCA acts as a pioneer factor in E2F-dependent gene activation and that a novel mechanism involving ANCCA bromodomain may contribute to cancer cell proliferation.
机译：组蛋白修饰被认为是通过细胞分裂的表观遗传记忆的载体。标记如何促进细胞周期依赖性基因表达的了解很少。进化上保守的AAA ATPase ANCCA（AAA核调节因子癌相关蛋白）/ ATAD2被鉴定为致癌基因 AIB1 / ACTR / SRC-3 < / em>和雌激素和雄激素受体的转录共调节剂，与肿瘤发生密切相关。我们在这里报告ANCCA直接与E2F1相互作用到E2F3，并且其N末端与E2F1的N和C末端都相互作用。 ANCCA优先通过其溴结构域与在赖氨酸14（H3K14ac）处乙酰化的H3缔合，是关键细胞周期基因表达和癌细胞增殖所必需的。 ANCCA与有丝分裂晚期的染色体相关，其在E2F的占有率目标是从G 1 到S过渡的峰值。令人惊讶地，需要ANCCA才能将特定的E2F募集到其靶标和宿主细胞因子1（HCF-1）-MLL组蛋白甲基转移酶复合物的染色质组装。 ANCCA耗竭导致基因激活相关的H3K4me3标记明显减少。溴结构域突变使ANCCA作为E2F辅助激活剂而失去其促进癌细胞增殖的能力，而肿瘤中ANCCA的过表达与肿瘤的生长相关。在一起，这些结果表明ANCCA充当E2F依赖性基因激活的先驱因子，并且涉及ANCCA bromodomain的新机制可能有助于癌细胞增殖。

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