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首页> 外文期刊>BMC Cancer >Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells
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Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells

机译：缺氧导致PC3前列腺癌细胞的选择性剪接发生显着变化以及CLK剪接因子激酶表达升高

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Mounting evidence suggests that one of the ways that cells adapt to hypoxia is through alternative splicing. The aim of this study was firstly to examine the effect of hypoxia on the alternative splicing of cancer associated genes using the prostate cancer cell line PC3 as a model. Secondly, the effect of hypoxia on the expression of several regulators of splicing was examined. PC3 cells were grown in 1% oxygen in a hypoxic chamber for 48?h, RNA extracted and sent for high throughput PCR analysis at the RNomics platform at the University of Sherbrooke, Canada. Genes whose exon inclusion rate PSI (ψ) changed significantly were identified, and their altered exon inclusion rates verified by RT-PCR in three cell lines. The expression of splice factors and splice factor kinases in response to hypoxia was examined by qPCR and western blotting. The splice factor kinase CLK1 was inhibited with the benzothiazole TG003. In PC3 cells the exon inclusion rate PSI (ψ) was seen to change by >?25% in 12 cancer-associated genes; MBP, APAF1, PUF60, SYNE2, CDC42BPA, FGFR10P, BTN2A2, UTRN, RAP1GDS1, PTPN13, TTC23 and CASP9 (caspase 9). The expression of the splice factors SRSF1, SRSF2, SRSF3, SAM68, HuR, hnRNPA1, and of the splice factor kinases SRPK1 and CLK1 increased significantly in hypoxia. We also observed that the splice factor kinase CLK3, but not CLK2 and CLK4, was also induced in hypoxic DU145 prostate, HT29 colon and MCF7 breast cancer cell lines. Lastly, we show that the inhibition of CLK1 in PC3 cells with the benzothiazole TG003 increased expression of the anti-apoptotic isoform caspase 9b. Significant changes in alternative splicing of cancer associated genes occur in prostate cancer cells in hypoxic conditions. The expression of several splice factors and splice factor kinases increases during hypoxia, in particular the Cdc-like splice factor kinases CLK1 and CLK3. We suggest that in hypoxia the elevated expression of these regulators of splicing helps cells adapt through alternative splicing of key cancer-associated genes. We suggest that the CLK splice factor kinases could be targeted in cancers in which hypoxia contributes to resistance to therapy.
机译：越来越多的证据表明，细胞适应缺氧的方式之一是通过选择性剪接。这项研究的目的首先是使用前列腺癌细胞系PC3作为模型，检查缺氧对癌症相关基因的选择性剪接的影响。其次，研究了缺氧对几种剪接调节子表达的影响。 PC3细胞在低氧舱中的1％氧气中生长48？h，提取RNA并送至加拿大舍布鲁克大学的RNomics平台进行高通量PCR分析。鉴定了外显子包含率PSI（ψ）显着变化的基因，并通过RT-PCR在三种细胞系中验证了其外显子包含率的改变。通过qPCR和蛋白质印迹检查了响应于缺氧的剪接因子和剪接因子激酶的表达。剪接因子激酶CLK1被苯并噻唑TG003抑制。在PC3细胞中，在12个与癌症相关的基因中，外显子包含率PSI（ψ）的变化大于25％。 MBP，APAF1，PUF60，SYNE2，CDC42BPA，FGFR10P，BTN2A2，UTRN，RAP1GDS1，PTPN13，TTC23和CASP9（胱天蛋白酶9）。缺氧时剪接因子SRSF1，SRSF2，SRSF3，SAM68，HuR，hnRNPA1的表达以及剪接因子激酶SRPK1和CLK1的表达显着增加。我们还观察到，在缺氧的DU145前列腺，HT29结肠和MCF7乳腺癌细胞系中也诱导了剪接因子激酶CLK3，但没有CLK2和CLK4。最后，我们显示苯并噻唑TG003对PC3细胞中CLK1的抑制作用增加了抗凋亡同工型半胱天冬酶9b的表达。在低氧条件下，前列腺癌细胞中发生癌症相关基因的可变剪接中的显着变化。在缺氧期间，几种剪接因子和剪接因子激酶的表达增加，特别是Cdc样剪接因子激酶CLK1和CLK3。我们建议，在缺氧状态下，这些剪接调节因子的表达升高，有助于细胞通过与癌症相关的关键基因的选择性剪接来适应细胞。我们建议，CLK剪接因子激酶可能是针对缺氧导致对治疗耐药的癌症。

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