Inhibition of Sox4 Increases the Sensitivity of Drug-resistant Melanoma Cells to Cisplatin through the P38 Signaling Pathway

Background: SRY-Box Transcription Factor 4 (Sox4) has been found to be overexpressed in a number of malignancies and is linked to medication resistance. The underlying mechanism of Sox4 in cisplatin-resistant melanomas, however, remains unknown. Methods: Immunohistochemistry (IHC) was used to examine the expression of Sox4 in melanoma, pigmented nevi, and normal skin tissue. Induction in vitro was used to create the cisplatin- resistant cell lines SK-MEL-28R and A375R. The CCK8 test was used to determine the IC50 values of cisplatin-resistant cells. Lentivirus shut down Sox4 in SK-MEL-28R and A375R cells. The Affymetrix GeneChip array was then utilized to detect changes in signaling pathways in SK-MEL-28R interfering with Sox4. Western blot, qRT-PCR, flow cytometry, and a caspase 3 activity kit were used to confirm the biological process of Sox4 impacting cisplatin resistance in melanoma. Results: Sox4 expression in melanoma was substantially higher than in pigmented nevus and normal skin tissue (p<0.05, p<0.01).SK-MEL-28R and A375R melanoma cisplatin-resistant strains were created effectively. They were 12.6 and 10.2 times more resistant to cisplatin, respectively than the parental cells. P-gp protein expression was substantially higher in cisplatinresistant strains than in parental strains. Sox4 inhibition lowered the IC50 value of cisplatin in resistant cells. (The IC50 value of SK-MEL-28R+NC was 122.7 mg/L and 24.4 mg/L for SKMEL- 28R+sh-sox4; the IC50 value of A375R+NC was 40.55 mg/L and 5.99 mg/L for A375R+sh-sox4). Meanwhile, Sox4 knockdown causes S phase arrest and enhanced caspase-3 activity in cisplatin-resistant melanoma cells. Sox4 knockdown led to activation of the P38 signaling pathway in resistant cells, according to genome-wide expression analysis, qRT-PCR, and Western blot detection. Conclusion: Our findings imply that inhibiting Sox4 can improve the sensitivity of drugresistant melanoma cells to cisplatin via the P38 signaling pathway, thus opening up a new route for melanoma treatment.