Akt regulates RSK2 to alter phosphorylation level of H2A.X in breast cancer.
Akt regulates RSK2 to alter phosphorylation level of H2A.X in breast cancer.
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Akt调节RSK2以改变乳腺癌中H2A.X的磷酸化水平。
DOI：
10.3892/ol.2021.12448
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发表时间：
2021-03
期刊：
影响因子：
2.9
通讯作者：
Kong FL
中科院分区：
文献类型：
--
作者：
Guo ZF;Kong FL
组蛋白H2 AX（H2A.X）是组蛋白H2 A家族的变体。H2A.X的磷酸化是DNA链断裂的标志，H2A.X的存在或缺失与肿瘤的易感性和耐药性密切相关。本研究发现丝氨酸/苏氨酸激酶Akt的活性与丝氨酸16位点磷酸化的H2A.X（H2A.X S16 ph）呈负相关，但这种负相关关系的机制尚不清楚。本研究的目的是阐明Akt和H2A.X S16 ph之间的作用机制以及该机制的确切作用。Western blot分析p-Akt与H2A.X S16 ph/p-RSK 2之间的调控关系，免疫沉淀和染色质免疫沉淀证实Akt、RSK 2和H2A.X在人乳腺癌细胞中联合收割机并相互作用。MTT法、软琼脂集落形成实验和细胞迁移实验检测Akt、RSK 2和H2 A. X相互作用对细胞增殖和迁移的影响。通过逆转录-定量PCR分析确定Akt、RSK 2和H2 A. X的相互作用对促癌基因如PSAT-1的影响。本研究表明，丝氨酸/苏氨酸激酶核糖体S6激酶2（RSK 2）作为H2A.X的激酶，可被Akt在Ser 19位点磷酸化。Akt通过正调控RSK 2的磷酸化，抑制H2A.X的磷酸化，从而影响RSK 2与底物组蛋白的亲和力，促进乳腺癌细胞的存活和迁移。总之，Akt介导的RSK 2磷酸化调节H2A.X的磷酸化，从而促进致癌活性。这一发现为了解乳腺癌的发病机制和治疗机制提供了新的见解。
Histone H2AX (H2A.X) is a variant of the histone H2A family. Phosphorylation of H2A.X is a marker of DNA strand breaks and the presence or absence of H2A.X is closely related to tumor susceptibility and drug resistance. The present study found that the activity of the serine/threonine kinase Akt was negatively associated with H2A.X phosphorylated at the Ser16 site (H2A.X S16ph), but the mechanism of the inverse relationship remains elusive. The aim of the present study was to elucidate the mechanism of action between Akt and H2A.X S16ph and the exact role of this mechanism. Western blot analysis was performed to detect the regulatory association between p-Akt and H2A.X S16ph/p-RSK2, and immunoprecipitation and chromatin immunoprecipitation were performed to prove that Akt, RSK2 and H2A.X combine and interact in human breast cancer cells. The changes of cellular proliferation and migration induced by the interaction of Akt, RSK2 and H2A.X was determined by MTT, soft agar colony formation and cell migration experiments. The effect of interaction of Akt, RSK2 and H2A.X on cancer-promoting genes, such as PSAT-1 was determined via reverse transcription-quantitative PCR analysis. The current study indicated that the serine/threonine kinase ribosomal S6 kinase 2 (RSK2) as a kinase of H2A.X could be phosphorylated by Akt at Ser19 site. Moreover, Akt positively regulated the phosphorylation of RSK2 to inhibit phosphorylation of H2A.X, thereby affecting the affinity between RSK2 and substrate histone, promoting the survival and migration of breast cancer cells. In conclusion, Akt-mediated phosphorylation of RSK2 regulated the phosphorylation of H2A.X, thereby promoting oncogenic activity. This finding provides new insights to understand the pathogenesis and treatment mechanisms of breast cancer.
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