SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-β-independent manner.
SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-β-independent manner.
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DOI：
10.1002/1878-0261.13487
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发表时间：
2024-01
影响因子：
6.6
通讯作者：
Robertson, Keith D.
中科院分区：
文献类型：
--
作者：
Wang, Tianchu;Wagner, Ryan T.;Hlady, Ryan A.;Pan, Xiaoyu;Zhao, Xia;Kim, Sungho;Wang, Liguo;Lee, Jeong-Heon;Luo, Huijun;Castle, Erik P.;Lake, Douglas F.;Ho, Thai H.;Robertson, Keith D.
关键词：
组蛋白赖氨酸 N-甲基转移酶 SETD2 (SETD2) 是唯一一种催化组蛋白 H3 (H3K36me3) 上赖氨酸 36 三甲基化的组蛋白甲基转移酶，在透明细胞肾细胞癌 (ccRCC) 中经常发生突变。 SETD2 突变和/或 H3K36me3 缺失与 ccRCC 患者的转移和不良预后相关。上皮间质转化（EMT）是驱动各种癌症类型侵袭和转移的主要途径。在这里，使用 SETD2 同基因的新型肾上皮细胞系，我们发现 SETD2 失活驱动 EMT，并以不依赖于转化生长因子 β 的方式促进迁移、侵袭和干细胞性。这种新发现的 EMT 程序部分是通过分泌因子（包括细胞因子和生长因子）以及转录重编程触发的。 RNA-seq 和转座酶可及染色质测序检测发现了 SETD2 丢失后上调的关键转录因子，包括 SOX2、POU2F2 (OCT2) 和 PRRX1，它们可以单独驱动 SETD2 野生型 (WT) 细胞中的 EMT 和干性表型。来自 SETD2 WT/突变体 ccRCC 的公开表达数据支持源自细胞系模型的 EMT 转录特征。总之，我们的研究表明 SETD2 通过细胞内在和细胞外在机制是 EMT 表型的关键调节因子，这有助于解释 SETD2 丢失与 ccRCC 转移之间的关联。组蛋白甲基转移酶 SETD2 在基因体处催化 H3K36me3，突变时与透明细胞肾细胞癌的不良预后相关。 SETD2 缺失会导致上皮间质转化 (EMT) 激活、整体 H3K36me3 缺失和染色质开放。 EMT 和干性表型本质上是由转录因子结合增加驱动的，外在则是由分泌因子介导的旁分泌效应驱动的。
Histone‐lysine N‐methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial‐to‐mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor‐beta‐independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA‐seq and assay for transposase‐accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild‐type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell‐intrinsic and cell‐extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis. Histone methyltransferase SETD2 catalyzes H3K36me3 at gene bodies and when mutated is associated with poor outcome in clear cell renal cell cancer. SETD2 loss results in activation of epithelial‐to‐mesenchymal transition (EMT), global H3K36me3 loss, and chromatin opening. The EMT and stemness phenotypes are driven intrinsically by increased transcription factor binding and extrinsically by paracrine effects mediated through secreted factors.
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