EGF/ERBB2 blocks the endoplasmic reticulum-associated degradation to facilitate chronic obstructive pulmonary disease development by decreasing FAM8A1 via up-regulating DNMT3A.

This work explored the mechanism of EGF affecting chronic obstructive pulmonary disease (COPD) development. The most significantly differentially expressed gene (DEG) and its downstream pathway was analyzed by Microarray analysis. By constructing COPD mouse and cell models, a series of in vivo and in vitro experiments were performed to verify whether EGF regulated COPD development by the ERBB2/DNMT3A/FAM8A1 signaling. As the most significantly DEG in COPD, EGF was associated with endoplasmic reticulum stress and exhibited the highest sensitivity as a biopredictive marker for COPD. ERBB2/DNMT3A/FAM8A1 signaling was the downstream pathway of EGF. In lung tissues of COPD mice, up-regulated EGF, ERBB2 and DNMT3A, but down-regulated FAM8A1 was found. EGF silencing improved pulmonary function and airway remodeling in COPD mice. AG-825 (ERBB2 inhibitor) relieved lung tissue damage and down-regulated GRP78, CHOP and Caspase-12 in lung tissues of COPD mice, but was counteracted by Eeyarestatin I (ERAD inhibitor). In COPD cell model, FAM8A1 up-regulation enhanced viability and proliferation; relieved apoptosis; and down-regulated GRP78, CHOP and Caspase-12. Eeyarestatin I abolished these influences of FAM8A1 on COPD cell model. DNMT3A knockdown increased FAM8A1 but decreased GRP78, CHOP and Caspase-12 in COPD cell model. FAM8A1 silencing or Eeyarestatin I treatment abrogated these influences of DNMT3A silencing. Similar to AG-825, EGF silencing enhanced viability; attenuated apoptosis; down-regulated DNMT3A; and up-regulated FAM8A1 in COPD cell model. EGF/ERBB2 represses endoplasmic reticulum-associated degradation to promote COPD development by reducing FAM8A1 via increasing DNMT3A. Blocking EGF/ERBB2 may help clinical treatment of COPD.