Lin Da-Wei, Carranza Francisco G, Borrego Stacey, Lauinger Linda, Dantas de Paula Lucas, Pulipelli Harika R, Andronicos Anna, Hertel Klemens J, Kaiser Peter
Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA.
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, USA.
Mol Metab. 2025 Mar;93:102103. doi: 10.1016/j.molmet.2025.102103. Epub 2025 Jan 23.
Many cancer cells depend on exogenous methionine for proliferation, whereas non-tumorigenic cells can divide in media supplemented with the metabolic precursor homocysteine. This phenomenon is known as methionine dependence of cancer or methionine addiction. The underlying mechanisms driving this cancer-specific metabolic addiction are poorly understood. Here we find that methionine dependence is associated with severe dysregulation of pre-mRNA splicing.
We used triple-negative breast cancer cells and their methionine-independent derivatives R8 to compare RNA expression profiles in methionine and homocysteine growth media. The data set was also analyzed for alternative splicing.
When tumorigenic cells were cultured in homocysteine medium, cancer cells failed to efficiently methylate the spliceosomal snRNP component SmD1, which resulted in reduced binding to the Survival-of-Motor-Neuron protein SMN leading to aberrant splicing. These effects were specific for cancer cells as neither Sm protein methylation nor splicing fidelity was affected when non-tumorigenic cells were cultured in homocysteine medium. Sm protein methylation is catalyzed by Protein Arginine Methyl Transferase 5 (Prmt5). Reducing methionine concentrations in the culture medium sensitized cancer cells to Prmt5 inhibition supporting a mechanistic link between methionine dependence of cancer and splicing.
Our results link nutritional demands to splicing changes and thereby provide a link between the cancer-specific metabolic phenomenon, described as methionine addiction over 40 years ago, with a defined cellular pathway that contributes to cancer cell proliferation.
许多癌细胞依赖外源性甲硫氨酸进行增殖，而非致瘤细胞可在补充有代谢前体同型半胱氨酸的培养基中分裂。这种现象被称为癌症的甲硫氨酸依赖性或甲硫氨酸成瘾。驱动这种癌症特异性代谢成瘾的潜在机制尚不清楚。在此，我们发现甲硫氨酸依赖性与前体mRNA剪接的严重失调有关。
我们使用三阴性乳腺癌细胞及其甲硫氨酸非依赖性衍生物R8来比较在甲硫氨酸和同型半胱氨酸生长培养基中的RNA表达谱。还对该数据集进行了可变剪接分析。
当致瘤细胞在同型半胱氨酸培养基中培养时，癌细胞无法有效地甲基化剪接体snRNP组分SmD1，这导致与运动神经元存活蛋白SMN的结合减少，从而导致异常剪接。这些效应是癌细胞特有的，因为当非致瘤细胞在同型半胱氨酸培养基中培养时，Sm蛋白甲基化和剪接保真度均未受影响。Sm蛋白甲基化由蛋白精氨酸甲基转移酶5（Prmt5）催化。降低培养基中甲硫氨酸浓度会使癌细胞对Prmt5抑制敏感，这支持了癌症的甲硫氨酸依赖性与剪接之间的机制联系。
我们的结果将营养需求与剪接变化联系起来，从而在40多年前被描述为甲硫氨酸成瘾的癌症特异性代谢现象与有助于癌细胞增殖的特定细胞途径之间建立了联系。
