MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2–TGFβ2–Smad2/3 signaling pathway in cervical cancer,Molecular Oncology

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MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2–TGFβ2–Smad2/3 signaling pathway in cervical cancer
Molecular Oncology ( IF 5.0 ) Pub Date : 2024-02-21 , DOI: 10.1002/1878-0261.13613
Han Zheng _{1,

2} , Mingchen Liu ₁ , Shu Shi ₁ , Hongxin Huang ₁ , Xingwen Yang _{1,

2} , Ziheng Luo _{1,

2} , Yarong Song _{1,

2} , Qiang Xu ₁ , Tingting Li ₃ , Lixiang Xue ₄ , Fengmin Lu ₁ , Jie Wang _{1,

2}

Affiliation

SRY-box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell-cycle-arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2–Smad2/3–p53–p21^WAF1/CIP1–Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4–MAPK (JNK/ERK/p38)–ATF2 and WT1–ATF2 pathways, which is dependent on its high-mobility group (HMG) domain. In addition, the SOX6-induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT-263 (navitoclax) and ABT-199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6-induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin-resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1–ATF2–TGFβ2 axis mediates SOX6-induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.

中文翻译：

MAP4K4 和 WT1 通过协同激活宫颈癌中 ATF2–TGFβ2–Smad2/3 信号通路介导 SOX6 诱导的细胞衰老

SRY-box 转录因子 6 ( SOX6 ) 是 SOX 基因家族的成员，通过诱导细胞周期停滞来抑制宫颈癌细胞的增殖。然而，SOX6 诱导的这些细胞周期停滞的宫颈癌细胞的最终细胞命运和意义仍不清楚。在这里，我们报道SOX6通过诱导细胞衰老来抑制宫颈癌细胞的增殖，这主要是通过促进转化生长因子β2（ TGFB2 ）基因表达并随后激活TGFβ2–Smad2/3–p53–p21 ^WAF1/CIP1介导的–Rb途径。 SOX6 通过 MAP4K4–MAPK (JNK/ERK/p38)–ATF2 和 WT1–ATF2 途径促进TGFB2基因表达，该途径依赖于其高迁移率基团 (HMG) 结构域。此外，SOX6诱导的衰老宫颈癌细胞对顺铂治疗具有抵抗力。 ABT-263（navitoclax）和ABT-199（venetoclax）两种经典的senolytics，可以特异性消除SOX6诱导的衰老宫颈癌细胞，从而显着提高顺铂耐药宫颈癌细胞的化疗敏感性。这项研究发现，MAP4K4/WT1–ATF2–TGFβ2 轴介导 SOX6 诱导的细胞衰老，这是改善宫颈癌化疗敏感性的一个有前景的治疗靶点。

更新日期：2024-02-23

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