Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030.
Department of Musculoskeletal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.
Proc Natl Acad Sci U S A. 2022 Apr 19;119(16):e2117857119. doi: 10.1073/pnas.2117857119. Epub 2022 Apr 11.
The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a–regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.
RB1 基因在人类癌症中经常发生突变，但它在肿瘤发生中的作用仍不完全明确。我们使用遗传性视网膜母细胞瘤（RB）的诱导多能干细胞（iPSC）模型，报告称剪接体是对 RB1 突变细胞中致癌应激的上调靶标。通过研究 RB iPSC 衍生的成骨细胞（OB）中的转录组和基因组占据情况，我们发现介导剪接体基因表达的 E2F3a 和拮抗 E2F3a 的 pRB 通过与其启动子或增强子结合，共同调节超过三分之一的剪接体基因。在 RB1 突变细胞中抑制剪接体的药理学抑制作用会导致全局内含子保留、细胞增殖减少和肿瘤发生受损。肿瘤标本研究和全基因组 TCGA（癌症基因组图谱）表达谱分析支持 pRB 和 E2F3a 在调节多种癌症类型（包括骨肉瘤（OS））中剪接体基因表达的临床相关性。高水平的 pRB/E2F3a 调节的剪接体基因与 OS 患者预后不良相关。总之，这些发现揭示了 pRB、E2F3a、剪接体和肿瘤发生之间未被发现的联系，指出剪接体机制可能是 pRB 缺陷型癌症的潜在广泛治疗弱点。
