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MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFß2-Smad2/3 signaling pathway in cervical cancer.
Zheng, Han; Liu, Mingchen; Shi, Shu; Huang, Hongxin; Yang, Xingwen; Luo, Ziheng; Song, Yarong; Xu, Qiang; Li, Tingting; Xue, Lixiang; Lu, Fengmin; Wang, Jie.
Afiliación
  • Zheng H; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Liu M; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • Shi S; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Huang H; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Yang X; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Luo Z; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Song Y; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • Xu Q; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Li T; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • Xue L; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • Lu F; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • Wang J; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Mol Oncol ; 18(5): 1327-1346, 2024 May.
Article en En | MEDLINE | ID: mdl-38383842
ABSTRACT
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 TGFß2-Smad2/3-p53-p21WAF1/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-TGFß2 axis mediates SOX6-induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Neoplasias del Cuello Uterino / Senescencia Celular / Proteína Smad2 / Factor de Transcripción Activador 2 / Factor de Crecimiento Transformador beta2 / Factores de Transcripción SOXD Límite: Animals / Female / Humans Idioma: En Revista: Mol Oncol Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Neoplasias del Cuello Uterino / Senescencia Celular / Proteína Smad2 / Factor de Transcripción Activador 2 / Factor de Crecimiento Transformador beta2 / Factores de Transcripción SOXD Límite: Animals / Female / Humans Idioma: En Revista: Mol Oncol Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos