AHSA1-DNAJB4 axis: A regulatory mechanism that initiates the ERAD pathway to facilitate endometrial cancer progression.

Endometrial cancer (EC) is a malignant neoplasm with a high prevalence, posing a significant threat to women's health and a substantial burden on the healthcare system. The endoplasmic reticulum-associated degradation (ERAD) pathway is essential for sustaining cellular homeostasis and tumorigenesis. This study elucidated the mechanisms of the DnaJ Heat Shock Protein Family (Hsp40) Member B4 (DNAJB4) and the activator of heat shock protein 90 (HSP90) ATPase activity 1 (AHSA1) in EC cells. DNAJB4 was knocked down in Ishikawa cells, and its impact on cellular biological functions was assessed using colony formation assays, flow cytometry, and western blot. The association between AHSA1 and DNAJB4 was identified using the Co-Immunoprecipitation (Co-IP) method. Ishikawa and RL95-2 cells overexpressing AHSA1 were generated, followed by functional assays and analysis of associated protein expressions. The knockdown of DNAJB4 markedly impeded the colony formation of Ishikawa and RL95-2 cells, enhanced apoptosis, and elevated the expressions of critical ERAD proteins X-box binding protein 1 (XBP-1s), activating transcription factor 4 (ATF4), C/EBP-homologous protein (CHOP), and growth arrest and DNA damage-inducible protein 34 (GADD34). AHSA1 bound to DNAJB4. The overexpression of AHSA1 enhanced the production of the DNAJB4 protein, facilitated cell colony formation, diminished cell apoptosis, and suppressed the expressions of ERAD-related proteins; however, the deletion of DNAJB4 negated these effects of AHSA1 overexpression. Collectively, AHSA1 and DNAJB4 cooperatively maintain efficient ERAD function, thereby alleviating endoplasmic reticulum stress and promoting EC progression.