NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis.

Abstract

PURPOSE:

Metastasis is the main cause of breast cancer mortality. Recent studies have proved that lipid metabolic reprogramming plays critical roles in breast cancer carcinogenesis and metastasis. We aim to identify critical lipid metabolism genes in breast cancer metastasis.

METHODS:

We designed and cloned a CRISPR pooled library containing lipid metabolic gene guide RNAs and performed a genetic screen in vivo. Transwell assay and animal experiments were used to evaluate cell metastatic ability in vitro or in vivo, respectively. We performed immunohistochemistry with breast cancer tissue microarray to study the clinical significance of NSDHL.

FINDINGS:

We identified a cholesterol metabolic enzyme, NSDHL, as a potential metastatic driver in triple-negative breast cancer. NSDHL was highly expressed in breast cancer tissues and predicted a poor prognosis. NSDHL knockdown significantly suppressed cell proliferation and migration. Mechanistically, NSDHL activated the TGFβ signaling pathway by inhibiting the endosomal degradation of TGFβR2. In addition, blocking the upstream metabolism of NSDHL with ketoconazole rescued cancer metastasis and TGFβR2 degradation. However, the inactivation of NSDHL (Y151X) did not rescue the migration ability and the TGFβR2 protein expression.

CONCLUSION:

Taken together, our findings established that NSDHL serves as a metastatic driver, and its function depends on its enzyme activity in cholesterol biosynthesis and is mediated by the NSDHL-TGFβR2 signal pathway. Our study indicated that NSDHL and steroid biosynthesis may serve as new drug targets for patients with advanced breast cancer.

• Authors: Mengting Chen, Yang Zhao, Xueli Yang, Yuanyuan Zhao, Qiqi Liu, Yang Liu, Yifeng Hou, Hefen Sun, Wei Jin
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 187 Issue 2 Pg. 349-362 (Jun 2021) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 33864166 (Publication Type: Journal Article)

Chemical References

• Transforming Growth Factor beta
• Cholesterol
• 3-Hydroxysteroid Dehydrogenases
• Nsdhl protein, human

Topics

• 3-Hydroxysteroid Dehydrogenases (metabolism)
• Animals
• Breast Neoplasms (genetics)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cholesterol
• Female
• Humans
• Neoplasm Metastasis
• Signal Transduction
• Transforming Growth Factor beta (genetics)
• Triple Negative Breast Neoplasms (genetics)