Declined RTN3 stabilizes DHCR7 to induce cholesterol-dependent tumor progression and MEK inhibitors insensitivity in thyroid cancer

Mechanism underlying thyroid cancer progression and treatment resistance remains an unsolved problem in clinical practice. Endoplasmic reticulum (ER) proteins modulate cell biosynthesis and mediate tumor progression, among which Reticulon 3 (RTN3) is verified to play important roles in cancers. However, its effect in thyroid cancer has not been clarified. Meanwhile, cholesterol is found to contribute to proliferation and drug resistance in many tumors. As ER is the primary site of cholesterol synthesis, we aimed to study how RTN3 regulates cholesterol concentration and influences tumor progression and sensitivity to MEK inhibitors in thyroid cancer. This study found that RTN3 is low-expressed in thyroid cancer, and is related to poor prognosis and insensitivity to MEK inhibitors. It binds to a cholesterol synthesis enzyme DHCR7 and promotes its ubiquitination. Downregulation of RTN3 lead to stabilization of DHCR7 and elevate cholesterol concentration, activating EGFR/ERK pathway and contributes to progression of thyroid cancer, which can be rescued by HMG-CoA reductase inhibitor Simvastatin. We identified RTN3 as a tumor suppressor and a biomarker of sensitivity to MEK inhibitors and verified the role of cholesterol in drug resistance. The combination of statins provides a novel therapeutic method in patients resistant to MEK inhibitors.