Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics.
Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics.
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DOI：
10.1016/j.canlet.2022.01.010
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发表时间：
2022-01
期刊：
影响因子：
9.7
通讯作者：
Shuai Ma;Jieyou Zhang;Qi Guo;Cheng Cao;Kaiwen Bao;Ling Liu;C. Chen;Zhe Liu;Jie Yang
中科院分区：
文献类型：
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作者：
Shuai Ma;Jieyou Zhang;Qi Guo;Cheng Cao;Kaiwen Bao;Ling Liu;C. Chen;Zhe Liu;Jie Yang
DNA损伤反应（DDR）途径通常可以防止基因组不稳定，DDR缺陷已被用于癌症治疗。我们已经报道了组蛋白去甲基化酶PHF8去甲基化TOPBP1 K118单甲基化（K118me1）来驱动ATR激酶的激活，ATR激酶是复制应激的主要调节因子之一。然而，这种生理信号的失调是否参与肿瘤发生仍不清楚。在这里，我们发现phf8促进的TOPBP1去甲基化在临床上与乳腺肿瘤发生和患者生存有关。phf8基因敲除小鼠的乳腺肿瘤生长缓慢，K118me1水平升高，ATR活性降低，染色体不稳定性增加。重要的是，我们发现PHF8-TOPBP1轴的破坏抑制了乳腺肿瘤的发生，并产生了乳腺肿瘤对PARP抑制剂（PARPi）和铂类药物的特异性易感性。临床肿瘤样本中缺失或截断的PHF8突变的CRISPR/Cas9突变模型表明，表达模仿变体的乳腺肿瘤细胞更容易受到PARPi的影响。总之，我们的研究支持了PHF8- topbp1信号通路作为PHF8- topbp1精通肿瘤靶向治疗的有希望的途径，并提供了PHF8功能丧失作为PARPis治疗指标的概念验证证据。
The DNA damage response (DDR) pathway generally protects against genome instability, and defects in DDR have been exploited therapeutically in cancer treatment. We have reported that histone demethylase PHF8 demethylates TOPBP1 K118 mono-methylation (K118me1) to drive the activation of ATR kinase, one of the master regulators of replication stress. However, whether dysregulation of this physiological signalling is involved in tumorigenesis remains unknown. Here, we showed PHF8-promoted TOPBP1 demethylation is clinically associated with breast tumorigenesis and patient survival. Mammary gland tumors fromPhf8knockout mice grow slowly and exhibit higher level of K118me1, lower ATR activity, and increased chromosomal instability. Importantly, we found that disruption of PHF8-TOPBP1 axis suppresses breast tumorigenesis and creates a breast tumor-specific vulnerability to PARP inhibitor (PARPi) and platinum drug. CRISPR/Cas9 mutation modelling of the deleted or truncated mutation of PHF8 in clinical tumor samples demonstrated breast tumor cells expressing the mimetic variants are more vulnerable to PARPi. Together, our study supports the pursuit of PHF8-TOPBP1 signalling pathway as promising avenues for targeted therapies of PHF8-TOPBP1 proficient tumors, and provides proof-of-concept evidence for loss-of-function of PHF8 as a therapeutic indicator of PARPis.