MAP4K4 and WT1 mediate SOX6‐induced cellular senescence by synergistically activating the ATF2–TGFβ2–Smad2/3 signaling pathway in cervical cancer
0301 basic medicine
cervical cancer
cisplatin
Mice, Nude
Uterine Cervical Neoplasms
Smad2 Protein
Protein Serine-Threonine Kinases
Mice
Transforming Growth Factor beta2
Cell Line, Tumor
cellular senescence
Animals
Humans
Smad3 Protein
RC254-282
Research Articles
Cellular Senescence
Cell Proliferation
Mice, Inbred BALB C
0303 health sciences
Activating Transcription Factor 2
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation, Neoplastic
senolytics
Female
SOX6
SOXD Transcription Factors
Signal Transduction
DOI:
10.1002/1878-0261.13613
Publication Date:
2024-02-22T02:25:35Z
AUTHORS (12)
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 TGFβ2–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–TGFβ2 axis mediates SOX6‐induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.
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