MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer.
MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer.
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DOI：
10.1038/s41419-021-04474-1
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发表时间：
2021-12-20
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Huang H;Han Q;Zheng H;Liu M;Shi S;Zhang T;Yang X;Li Z;Xu Q;Guo H;Lu F;Wang J
近40%的宫颈癌患者对自噬诱导的新辅助化疗反应不佳，但其潜在机制尚未完全阐明。我们之前发现，y相关高迁移率组框6 （SOX6）的性别决定区是几种肿瘤的抑癌基因或癌基因，可诱导宫颈癌的自噬。因此，本研究旨在探讨sox6诱导自噬的机制及其在宫颈癌铂基化疗中的潜在意义。首先，我们发现SOX6可以通过其HMG结构域促进宫颈癌细胞自噬。有丝裂原活化蛋白激酶激酶激酶激酶激酶激酶激酶4 （MAP4K4）基因被确定为SOX6的直接靶基因，该基因通过将SOX6蛋白的HMG结构域与MAP4K4基因启动子内的双结合位点结合而转录上调。MAP4K4通过抑制PI3K-Akt-mTOR通路和激活MAPK/ERK通路介导sox6诱导的自噬。此外，在体外和体内，sox6诱导的自噬可以降低宫颈癌细胞对顺铂化疗的敏感性，而自噬特异性抑制剂和MAP4K4抑制剂分别可以逆转这一现象。此外，顺铂本身可以促进宫颈癌细胞内源性SOX6的表达，进而促进map4k4介导的自噬，这可能反过来降低这些细胞对顺铂治疗的敏感性。这些发现揭示了sox6诱导自噬的潜在机制和潜在意义，并为使用MAP4K4抑制剂或自噬特异性抑制剂使宫颈癌细胞对铂类化疗增敏提供了新的思路。
There are nearly 40% of cervical cancer patients showing poor response to neoadjuvant chemotherapy that can be induced by autophagy, however, the underlying mechanism has not yet been fully clarified. We previously found that Sex-determining region of Y-related high-mobility-group box 6 (SOX6), a tumor suppressor gene or oncogene in several cancers, could induce autophagy in cervical cancer. Accordingly, this study aims to investigate the mechanism of SOX6-induced autophagy and its potential significance in the platinum-based chemotherapy of cervical cancer. Firstly, we found that SOX6 could promote autophagy in cervical cancer cells depending on its HMG domain. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) gene was identified as the direct target gene of SOX6, which was transcriptionally upregulated by binding the HMG domain of SOX6 protein to its double-binding sites within MAP4K4 gene promoter. MAP4K4 mediated the SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR pathway and activating MAPK/ERK pathway. Further, the sensitivity of cervical cancer cells to cisplatin chemotherapy could be reduced by the SOX6-induced autophagy in vitro and in vivo, while such a phenomenon could be turned over by autophagy-specific inhibitor and MAP4K4 inhibitor, respectively. Moreover, cisplatin itself could promote the expression of endogenous SOX6 and subsequently the MAP4K4-mediated autophagy in cervical cancer cells, which might in turn reduce the sensitivity of these cells to cisplatin treatment. These findings uncovered the underlying mechanism and potential significance of SOX6-induced autophagy, and shed new light on the usage of MAP4K4 inhibitor or autophagy-specific inhibitor for sensitizing cervical cancer cells to the platinum-based chemotherapy.
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