DERL2 (derlin 2) stabilizes BAG6 (BAG cochaperone 6) in chemotherapy resistance of cholangiocarcinoma

DERL2 (derlin 2) is a critical component of the endoplasmic reticulum quality control pathway system whose mutations play an important role in carcinogenesis, including cholangiocarcinoma (CHOL). However, its role and its underlying mechanism have yet to be elucidated. Herein, we revealed that DERL2 was highly expressed in CHOL and considered as an independent prognostic indicator for inferior survival in CHOL. DERL2 ectopically expressed in CHOL cells promoted cell proliferation and colony formation rates, and depleting DERL2 in CHOL cells curbed tumor growth in vitro and in vivo. More interestingly, the knockout of DERL2 augmented the growth-inhibitory effect of gemcitabine chemotherapy on CHOL cells by inducing cell apoptosis. Mechanistically, we discovered that DERL2 interacted with BAG6 (BAG cochaperone 6), thereby extending its half-life and reinforcing the oncogenic role of BAG6 in CHOL progression.