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

Anwen Ren1,2, Nan Feng3,4, Tinglin Yang1

  • 1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cell Death & Disease
|March 12, 2026
PubMed

Insights

Reticulon 3 (RTN3) acts as a tumor suppressor in thyroid cancer by regulating cholesterol synthesis. Lower RTN3 levels promote cancer progression and resistance to MEK inhibitors, suggesting statins as a potential therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Thyroid cancer progression and treatment resistance mechanisms are poorly understood.
  • Endoplasmic reticulum (ER) proteins, including Reticulon 3 (RTN3), influence tumor progression.
  • Cholesterol metabolism is implicated in cancer proliferation and drug resistance.

Purpose of the Study:

  • To investigate the role of RTN3 in regulating cholesterol concentration in thyroid cancer.
  • To determine RTN3's impact on thyroid cancer progression and sensitivity to MEK inhibitors.
  • To explore potential therapeutic strategies targeting cholesterol synthesis.

Main Methods:

  • Analysis of RTN3 expression in thyroid cancer tissues.
  • Investigation of RTN3 binding to DHCR7 and its effect on DHCR7 ubiquitination.
  • Assessment of cholesterol levels and EGFR/ERK pathway activation.
  • Evaluation of Simvastatin's effect on cancer progression and drug sensitivity.

Main Results:

  • RTN3 is underexpressed in thyroid cancer, correlating with poor prognosis and MEK inhibitor resistance.
  • RTN3 binds to DHCR7, promoting its ubiquitination and degradation.
  • Reduced RTN3 stabilizes DHCR7, increasing cholesterol levels and activating the EGFR/ERK pathway.
  • Simvastatin treatment rescued the effects of RTN3 downregulation, reducing tumor progression.

Conclusions:

  • RTN3 functions as a tumor suppressor in thyroid cancer.
  • RTN3 is a potential biomarker for predicting sensitivity to MEK inhibitors.
  • Elevated cholesterol levels driven by RTN3 deficiency contribute to thyroid cancer progression and drug resistance.
  • Combination therapy with statins may offer a novel approach for treating MEK inhibitor-resistant thyroid cancer.

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