Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells
Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells
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DOI：
10.1098/rsob.190052
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发表时间：
2019-04-01
期刊：
影响因子：
5.8
通讯作者：
Cowling, Victoria H.
中科院分区：
文献类型：
--
作者：
Dunn, Sianadh;Lombardi, Olivia;Cowling, Victoria H.
目前正在研究基因表达的基本机制作为癌症治疗的目标。一个这样的基本过程是在前 mRNA 上添加帽子，它招募 mRNA 加工和翻译起始的介体。帽的成熟涉及由 RNMT（RNA 鸟嘌呤 7 甲基转移酶）催化的 mRNA 帽鸟苷 N-7 甲基化。在一组乳腺癌细胞系中，我们研究了是否所有细胞系都同样依赖 RNMT 进行增殖。当细胞 RNMT 活性实验性降低 50% 时，未转化的乳腺上皮细胞的增殖率没有变化，而乳腺癌细胞系的子集则表现出增殖减少和凋亡增加。大多数表现出对 RNMT 依赖性增强的细胞系都含有 PIK3CA 致癌突变，PIK3CA 编码 PI3K α 的 p110 α 亚基。相反，所有对 RNMT 耗竭不敏感的细胞系均表达野生型 PIK3CA。致癌 PIK3CA 突变体的表达可增加 PI3K p110 α 活性，足以增加对 RNMT 的依赖性。相反，抑制 PI3K α 可逆转对 RNMT 的依赖，表明 PI3K α 信号传导是必需的。总的来说，这些发现提供了支持 RNMT 作为乳腺癌治疗靶点的证据，并表明针对 RNMT 的治疗在 PIK3CA 突变背景中最有价值。
Basic mechanisms in gene expression are currently being investigated as targets in cancer therapeutics. One such fundamental process is the addition of the cap to pre-mRNA, which recruits mediators of mRNA processing and translation initiation. Maturation of the cap involves mRNA cap guanosine N-7 methylation, catalysed by RNMT (RNA guanine-7 methyltransferase). In a panel of breast cancer cell lines, we investigated whether all are equivalently dependent on RNMT for proliferation. When cellular RNMT activity was experimentally reduced by 50%, the proliferation rate of non-transformed mammary epithelial cells was unchanged, whereas a subset of breast cancer cell lines exhibited reduced proliferation and increased apoptosis. Most of the cell lines which exhibited enhanced dependency on RNMT harboured oncogenic mutations in PIK3CA, which encodes the p110 alpha subunit of PI3K alpha. Conversely, all cell lines insensitive to RNMT depletion expressed wild-type PIK3CA. Expression of oncogenic PIK3CA mutants, which increase PI3K p110 alpha activity, was sufficient to increase dependency on RNMT. Conversely, inhibition of PI3K alpha reversed dependency on RNMT, suggesting that PI3K alpha signalling is required. Collectively, these findings provide evidence to support RNMT as a therapeutic target in breast cancer and suggest that therapies targeting RNMT would be most valuable in a PIK3CA mutant background.