TAOK3 Facilitates Esophageal Squamous Cell Carcinoma Progression and Cisplatin Resistance Through Augmenting Autophagy Mediated by IRGM

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers because of its robust aggressive phenotype and chemoresistance. TAO kinase belongs to mitogen-activated protein kinases, which mediate drug resistance in multiple cancers. However, the role of TAO kinase in ESCC progression and chemoresistance has never been explored. Here, it is reported that TAOK3 augments cell autophagy and further promotes ESCC progression and chemoresistance. Mechanistically, TAOK3 phosphorylates KMT2C at S4588 and strengthens the interaction between KMT2C and ETV5. Consequently, the nuclear translocation of KMT2C is increased, and the transcription of autophagy-relevant gene IRGM is further upregulated. Additionally, the inhibitor SBI-581 can significantly suppress cell autophagy mediated by TAOK3 and synergizes with cisplatin to treat ESCC in vitro and in vivo. TAOK3 can augment autophagy and chemo-resistance in esophageal squamous cell carcinoma (ESCC) cells mechanically by phosphorylating KMT2C and promoting the interaction between KMT2C and ETV5. Consequently, the nuclear translocation of KMT2C is increased, and IRGM transcription is promoted. Particularly, a specific inhibitor of TAOK3, SBI-581, is identified, which can synergize with cisplatin and subsequently enhance the effectiveness of chemotherapy in ESCC.image