EMC2 promotes breast cancer progression and enhances sensitivity to PDK1/AKT inhibition by deubiquitinating ENO1.

Breast cancer is the most common malignant tumor worldwide, causing 685,000 deaths in 2020, and this number continues to rise. Identifying the molecular mechanisms driving breast cancer progression and potential therapeutic targets are currently urgent issues. Our previous work and bioinformatics analysis shows that the expression of Endoplasmic Reticulum Membrane Protein Complex Subunit 2 (EMC2) is up-regulated in breast cancer and is correlated with shortened overall survival of patients. However, the mechanism of EMC2 in breast cancer is yet to be elucidated. In this study, we identified that EMC2 promotes breast cancer proliferation and metastasis by activating the PDK1/AKT (T308)/mTOR (S2448) signaling pathway and can serve as a candidate target for PDK1/AKT inhibition. Mechanistically, EMC2 serves as a "scaffold" protein to recruit the deubiquitinating enzyme (DUB) USP7 for ENO1 deubiquitylation to stabilize its expression, thereby initiating downstream B-MYB/PDK1/AKT (T308)/mTOR (S2448) signal cascade. Silencing EMC2 significantly weaken the proliferation/metastasis potential of breast cancer in vitro and in vivo, but made tumor cell sensitive to PDK1/AKT inhibition. Overexpression of EMC2 leads to exactly the opposite result. This study reveals the EMC2/USP7/ENO1/B-MYB protumorigenic axis in breast cancer and identifies EMC2 as a candidate target for PDK1/AKT inhibitory therapy.