PDF(Pubmed)
Abstract：
Splicing factor polyglutamine binding protein-1 (PQBP1) is abundantly expressed in the central nervous system during development, and mutations in the gene cause intellectual disability. However, the roles of PQBP1 in cancer progression remain largely unknown. Here, it is shown that PQBP1 overexpression promotes tumor progression and indicates worse prognosis in ovarian cancer. Integrative analysis of spyCLIP-seq and RNA-seq data reveals that PQBP1 preferentially binds to exon regions and modulates exon skipping. Mechanistically, it is shown that PQBP1 regulates the splicing of genes related to the apoptotic signaling pathway, including BAX. PQBP1 promotes BAX exon 2 skipping to generate a truncated isoform that undergoes degradation by nonsense-mediated mRNA decay, thus making cancer cells resistant to apoptosis. In contrast, PQBP1 depletion or splice-switching antisense oligonucleotides promote exon 2 inclusion and thus increase BAX expression, leading to inhibition of tumor growth. Together, the results demonstrate an oncogenic role of PQBP1 in ovarian cancer and suggest that targeting the aberrant splicing mediated by PQBP1 has therapeutic potential in cancer treatment.
摘要：
剪接因子聚谷氨酰胺结合蛋白-1(PQBP1)在发育过程中在中枢神经系统中大量表达,基因突变会导致智力残疾。然而,PQBP1在癌症进展中的作用在很大程度上仍然未知.这里,结果表明，PQBP1过表达促进卵巢癌的肿瘤进展，并表明预后较差。对spyCLIP-seq和RNA-seq数据的整合分析表明，PQBP1优先结合外显子区域并调节外显子跳跃。机械上,PQBP1调控凋亡信号通路相关基因的剪接,包括BAX.PQBP1促进BAX外显子2跳跃以产生截短的同种型，该同种型通过无义介导的mRNA降解，从而使癌细胞抵抗凋亡。相比之下,PQBP1缺失或剪接转换反义寡核苷酸促进外显子2包合，从而增加BAX表达，导致抑制肿瘤生长。一起,结果证明了PQBP1在卵巢癌中的致癌作用,并提示靶向PQBP1介导的异常剪接在癌症治疗中具有治疗潜力.
