Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China.
Nat Commun. 2022 Apr 21;13(1):2192. doi: 10.1038/s41467-022-29899-w.
Smad nuclear-interacting protein 1 (SNIP1) is a transcription repressor related to the TGF-β signaling pathway and associates with c-MYC, a key regulator of cell proliferation and tumor development. Currently, the mechanism by which SNIP1 regulates tumorigenesis and cancer metastasis is unknown. Here, we identify that SNIP1 is a non-histone substrate of lysine methyltransferase KMT5A, which undergoes KMT5A-mediated mono-methylation to promote breast cancer cell growth, invasion and lung metastasis. Mechanistically, we show KMT5A-mediated K301 methylation of SNIP1 represents a sensing signal to release histone acetyltransferase KAT2A and promotes the interaction of c-MYC and KAT2A, and the recruitment of c-MYC/KAT2A complex to promoter of c-MYC targets. This event ultimately inhibits the Hippo kinase cascade to enhance triple-negative breast cancer (TNBC) metastasis by transcriptionally activating MARK4. Co-inhibition of KMT5A catalytic activity and YAP in TNBC xenograft-bearing animals attenuates breast cancer metastasis and increases survival. Collectively, this study presents an KMT5A methylation-dependent regulatory mechanism governing oncogenic function of SNIP1.
Smad 核内相互作用蛋白 1（SNIP1）是与 TGF-β 信号通路相关的转录抑制剂，与细胞增殖和肿瘤发生的关键调节因子 c-MYC 相关。目前，SNIP1 调节肿瘤发生和癌症转移的机制尚不清楚。在这里，我们确定 SNIP1 是赖氨酸甲基转移酶 KMT5A 的非组蛋白底物，它经历 KMT5A 介导的单甲基化以促进乳腺癌细胞生长、侵袭和肺转移。在机制上，我们表明 KMT5A 介导的 SNIP1 的 K301 甲基化代表一种释放组蛋白乙酰转移酶 KAT2A 的感应信号，并促进 c-MYC 和 KAT2A 的相互作用，以及 c-MYC/KAT2A 复合物募集到 c-MYC 靶标的启动子。这一事件最终通过转录激活 MARK4 抑制 Hippo 激酶级联反应，从而增强三阴性乳腺癌（TNBC）的转移。在携带 TNBC 异种移植的动物中，同时抑制 KMT5A 的催化活性和 YAP，可减轻乳腺癌转移并提高存活率。总之，这项研究提出了一种 KMT5A 依赖性甲基化调节机制，该机制控制 SNIP1 的致癌功能。
