The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K.
The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K.
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DOI：
10.15212/amm-2022-0013
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发表时间：
2022-05
期刊：
影响因子：
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通讯作者：
Franklin Mayca Pozo;T. Hunter;Youwei Zhang
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文献类型：
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作者：
Franklin Mayca Pozo;T. Hunter;Youwei Zhang
经典的磷脂酰肌醇3 - 激酶（PI3Ks）是p110和p85的异二聚体。PIK3CA是编码催化性p110α亚基的基因，是人类癌症中最常发生突变的癌基因之一，热点突变发生在螺旋结构域或激酶结构域。具有这两种PIK3CA突变类型的肿瘤表现出重叠但又不同的表型；然而，潜在机制仍不清楚。在最近的一篇发表文献[1]中，郝等人揭示了关于PI3K p85β调节亚基在促进PIK3CA螺旋结构域突变驱动的癌症进展方面令人兴奋的发现。作者发现，只有在携带PIK3CA螺旋结构域突变的癌细胞中，p85β才会从PI3K复合物中解离并转位到细胞核中。破坏p85β的核定位可抑制具有PIK3CA螺旋结构域突变的癌细胞在小鼠体内的肿瘤生长。从机制上讲，他们巧妙地表明，核内的p85β招募去泛素化酶USP7以稳定组蛋白甲基转移酶EZH1/2，从而导致H3K27三甲基化和基因转录增强。将一种EZH抑制剂与一种PI3K抑制剂联合使用，可特异性地导致具有PIK3CA螺旋结构域突变的小鼠异种移植肿瘤消退。这些发现阐明了p85β在肿瘤发展中以前未被描述的功能，并提出了一种针对具有PIK3CA螺旋突变的肿瘤的有效方法。
The classical phosphatidylinositol 3-kinases (PI3Ks) are heterodimers of p110 and p85. PIK3CA, the gene encoding the catalytic p110α subunit, is one of the most frequently mutated oncogenes in human cancers with hot spot mutations occurring in the helical domain or in the kinase domain. Tumors with these two types of PIK3CA mutations show overlapping yet distinct phenotypes; however, the underlying mechanisms remain unclear. In a recent publication [1], Hao et al revealed exciting findings about the PI3K p85β regulatory subunit in promoting PIK3CA helical domain mutation-driven cancer progression. The authors found that p85β disassociated from the PI3K complex and translocated into the nucleus only in cancer cells harboring PIK3CA helical domain mutations. Disrupting nuclear localization of p85β suppressed mouse tumor growth of cancer cells with PIK3CA helical domain mutation. Mechanistically, they elegantly showed that nuclear p85β recruited the deubiquitinase USP7 to stabilize the histone methyltransferases EZH1/2, leading to enhanced H3K27 trimethylation and gene transcription. Combining an EZH inhibitor with a PI3K inhibitor specifically resulted in regression of mouse xenograft tumors with PIK3CA helical domain mutations. These findings illustrate a previously uncharacterized function of p85β in tumor development and suggest an effective approach to target tumors with PIK3CA helical mutations.