Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of data sets in the Cancer Dependency Map Project revealed that many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and cleavage under targets and release using nuclease assay (CUT&RUN) results identified pathways directly regulated by ADA2B including MTORC1 signaling and oncogenic programs driven by MYC, E2F, and MM-specific MAF. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found that the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.

中文翻译：

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SAGA 乙酰转移酶模块是维持多发性骨髓瘤中 MAF 和 MYC 致癌基因表达程序所必需的


尽管治疗方法最近取得了进展，多发性骨髓瘤（MM）仍然是一种无法治愈的恶性肿瘤。表观遗传因素导致多发性骨髓瘤的发生、进展、复发和克隆异质性，但我们对多发性骨髓瘤发生的表观遗传机制的了解还远未完成。 SAGA 复合物充当转录中的共激活子并催化乙酰化和去泛素化。对癌症依赖性图项目中数据集的分析表明，许多 SAGA 组件在 MM 中是选择性依赖性的。为了定义 SAGA 特有的功能，我们重点关注 ADA2B，它是赖氨酸乙酰转移酶 (KAT) 模块中唯一在 SAGA 中专门发挥作用的亚基。整合 RNA 测序 (RNA-seq)、转座酶可及染色质测序分析 (ATAC-seq) 以及使用核酸酶分析进行靶标切割和释放 (CUT&RUN) 结果确定了由 ADA2B 直接调节的途径，包括 MTORC1 信号传导和致癌程序驱动通过 MYC、E2F 和 MM 特定的 MAF。我们发现 ADA2B 被招募到 MAF 和 MYC 基因靶点，并且 MAF 与 MM 细胞中的 MYC 共享大部分靶点。此外，我们发现 ADA2B 的 SANT 结构域是与 GCN5 和 PCAF 乙酰转移酶相互作用、掺入 SAGA 以及 ADA2B 蛋白稳定性所必需的。我们的研究结果揭示了以前未知的 SAGA KAT 模块依赖性控制 MM 细胞生长的机制，揭示了可能用于未来 MM 治疗开发的漏洞。