Li Jing, Li Peiyu, Brachtlova Tereza, van der Meulen-Muileman Ida H, Dekker Henk, Kumar Vishal S, Fransen Marieke, Bahce Idris, Felley-Bosco Emanuela, van Beusechem Victor W
Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands.
Int J Mol Sci. 2024 Dec 6;25(23):13131. doi: 10.3390/ijms252313131.
The core spliceosome Sm proteins are gaining attention as potential targets for cancer treatment. Here, we evaluate this, with focus on SmD2. A pan-cancer analysis including 26 solid tumor types revealed that the SmD2-encoding gene was overexpressed in almost all cancers. In several cancers, high expression was associated with a poor prognosis. To investigate the vulnerability of human cells to the loss of SmD2 expression, we silenced using a short hairpin-expressing lentiviral vector in established cancer cell lines; in short-term cultured melanoma cells; and in several normal cell cultures, including cancer-associated fibroblasts cultured from non-small cell lung cancer resections. Additionally, we analyzed publicly available cell viability datasets for the dependency of cancer cell lines to SmD2 expression. Together, these studies clearly established SmD2 as a cancer-selective lethal target. Delving into genes with similar essentiality profiles to , we uncovered the intersected lethal stress between the loss of SmD2 and the loss of gene products participating in not only different mRNA processing steps including mRNA splicing, but also processes for coordinated protein production, as well as mitosis. Furthermore, we could correlate expression to the responses of cancer cells to several FDA-approved anti-tumor drugs, especially to drugs inhibiting the cell cycle. Overall, our study confirms the anticipated role for targeting SmD2 in cancer treatment and reveals non-canonical SmD2 functions beyond mRNA splicing that could contribute to the dependency of cancer cells to high expression.
核心剪接体Sm蛋白作为癌症治疗的潜在靶点正受到关注。在此，我们以SmD2为重点对此进行评估。一项涵盖26种实体瘤类型的泛癌分析显示，编码SmD2的基因在几乎所有癌症中均过度表达。在几种癌症中，高表达与不良预后相关。为了研究人类细胞对SmD2表达缺失的易感性，我们在已建立的癌细胞系、短期培养的黑色素瘤细胞以及几种正常细胞培养物（包括从非小细胞肺癌切除标本中培养的癌症相关成纤维细胞）中，使用表达短发夹的慢病毒载体使其沉默。此外，我们分析了公开可用的细胞活力数据集，以了解癌细胞系对SmD2表达的依赖性。综合这些研究清楚地确定SmD2为癌症选择性致死靶点。深入研究与SmD2具有相似必需性特征的基因，我们发现SmD2缺失与参与不同mRNA加工步骤（包括mRNA剪接）、协调蛋白质生产过程以及有丝分裂的基因产物缺失之间存在交叉致死应激。此外，我们能够将SmD2表达与癌细胞对几种FDA批准的抗肿瘤药物的反应相关联，特别是与抑制细胞周期的药物相关联。总体而言，我们的研究证实了靶向SmD2在癌症治疗中的预期作用，并揭示了SmD2在mRNA剪接之外的非经典功能，这些功能可能导致癌细胞对高SmD2表达的依赖性。
