Collectively, these findings indicate that squamocin activates the UPS via UBA6 (E1), facilitating ubiquitin charging to UBE2Z (E2) and increasing the activities of FBXW7 (E3) to degrade both EZH2 and MYC, in an HSP90α‐dependent manner in HNSCC. This evidence concerns the gene UBA6 and head and neck squamous cell carcinoma.