MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer
Hongxin Huang, Qin Han, Zheng Han, Mingchen Liu, Shi Shu, Ting Zhang, Xingwen Yang, Zhongqing Li, Qiang Xu, Hongyan Guo, Fengmin Lu, Jie Wang
Abstract
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.