The Ku70-SIX1-GPT2 axis regulates alpha-ketoglutarate metabolism to drive progression of prostate cancer.

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Oncogene Pub Date : 2024-11-02 DOI:10.1038/s41388-024-03209-8

Hongbiao Huang, Xuefen Zhuang, Shusha Yin, Wenshuang Sun, Ji Cheng, E-Ying Peng, Yujie Xiang, Xiaoyue He, Mengfan Tang, Yuting Li, Yu Yao, Yuanfei Deng, Qing Liu, Zhenlong Shao, Xiaohong Xia, Gengxi Cai, Yuning Liao

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Abstract

Sine oculis homeobox homolog 1 (SIX1) is a new identified cancer driver in the development of prostate cancer (PC). However, the upstream regulatory mechanisms for SIX1 reactivation in cancer remains elusive. Here, we found that Ku70 robustly interacts with SIX1 in the nucleus of PC cells. The HD domain of SIX1 and the DBD domain of Ku70 are required for formation of Ku70-SIX1 complex. 20 groups of hydrogen bonds were identified in this complex by molecular dynamics simulation. Depletion of Ku70/SIX1 notably abrogates the proliferation and migration of PC. Further studies revealed that SIX1 is recruited to the promoter region on glutamate-pyruvate transaminase 2 (GPT2). Ku70 enhances the SIX1-mediated transcriptional activation on GPT2, thereby facilitating the generation of alpha-ketoglutarate (α-KG). In addition, formation of the Ku70-SIX1 complex promotes GPT2-dependent cell proliferation and migration in PC. Moreover, the expression of GPT2 is upregulated and strongly correlated with the expression of Ku70/SIX1 in PC tissues. In summary, our findings not only provide insight into the mechanistic interactions between Ku70 and SIX1, but also highlight the significance of the Ku70-SIX1-GPT2 axis for α-KG metabolism and PC carcinogenesis.

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Ku70-SIX1-GPT2轴调节α-酮戊二酸代谢，推动前列腺癌的进展。

Sine oculis homeobox homolog 1（SIX1）是前列腺癌（PC）发病过程中新发现的癌症驱动因素。然而，SIX1 在癌症中重新激活的上游调控机制仍不明确。在这里，我们发现 Ku70 与 PC 细胞核中的 SIX1 有很强的相互作用。SIX1 的 HD 结构域和 Ku70 的 DBD 结构域是 Ku70-SIX1 复合物形成的必要条件。分子动力学模拟确定了该复合物中的 20 组氢键。去除了 Ku70/SIX1 后，PC 的增殖和迁移明显减弱。进一步研究发现，SIX1 被招募到谷氨酸-丙酮酸转氨酶 2（GPT2）的启动子区域。Ku70 可增强 SIX1 介导的 GPT2 转录激活，从而促进α-酮戊二酸（α-KG）的生成。此外，Ku70-SIX1 复合物的形成促进了 PC 中依赖于 GPT2 的细胞增殖和迁移。此外，PC 组织中 GPT2 的表达上调，并与 Ku70/SIX1 的表达密切相关。总之，我们的研究结果不仅深入揭示了Ku70和SIX1之间的机理相互作用，还强调了Ku70-SIX1-GPT2轴对α-KG代谢和PC癌变的重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.