MLLT3 Regulates Melanoma Stemness and Progression by Inhibiting HMGB1 Nuclear Entry and MAGEA1 M⁵C Modification

Abstract Melanoma stem cells are a kind of cells with self‐renewal and multi‐directional differentiation potential. They are one of the key factors in the occurrence, development and metastasis of melanoma. This study demonstrates that MLLT3 is a transcription factor that regulates the stemness and progression of melanoma. MLLT3 interacted with HMGB1 to inhibit its entry into the nucleus, MLLT3 interacted with YBX1 to inhibit its reading of m⁵C of MAGEA1, thereby inhibiting the mRNA stability of MAGEA1, and directly transcribed P53 to inhibit the stemness, proliferation and metastasis of melanoma cells. This study further explored the potential mechanism of the interaction between miR‐542‐3p/miR‐3922‐3p and MLLT3. Furthermore, the scRNA‐seq of melanoma cells with MLLT3 knock‐out resulted in important changes in cell subsets, activating the TP53 and MAPK pathways and transforming into stem cells. The results indicate that the transcription factor MLLT3 is a suppressor gene that regulates the stemness and progression of melanoma, and is expected to become a target for melanoma therapy.