SIAH1 ubiquitination-modified HMGCR inhibits lung cancer progression and promotes drug sensitivity through cholesterol synthesis

Abstract

Backgrounds Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide. Deep understanding of chemoresistance will lead to remarkable progress in lung cancer treatment strategy. Cholesterol accumulation was associated with cisplatin resistance in lung cancer treatment. And we found the degree of cisplatin resistance was correlated with the expression of the cholesterol synthesis HMGCR. Methods We analyzed a group of 42 lung cancer patients who received cisplatin treatment after lung resection surgery. The expression of HMGCR and its correlation with cholesterol in lung cancer cell lines were determined by qRT-PCR and ELISA analyses. We focus on the function and mechanism of HMGCR in lung cancer and reveal that knockdown of HMGCR expression inhibits the proliferation, colony formation, and migration of lung cancer cell lines in vitro or in vivo and dramatically enhances the efficacy of cisplatin. Results Through mechanism studies, we illustrate that SIAH1, an E3 ubiquitin-protein ligase, ubiquitination modifies HMGCR and inhibits efflux protein activity via regulating cholesterol synthesis. In vivo experiments showed that SIAH1 overexpression or using HMGCR knockdown retard tumor growth and enhanced the efficacy of cisplatin. In summary, HMGCR affects cholesterol metabolism by regulating key enzymes in cholesterol synthesis, thereby reducing drug sensitivity. Conclusion This study indicates that lung cancer patients with lower HMGCR levels may lead to a better prognosis and provide a potential treatment by SIAH1 overexpression for lung cancer patients with cisplatin resistance.

Advances of E3 ligases in lung cancer

“…With BCA2 zinc-finger domain, ring finger protein 115 (RNF115) ubiquitinates β-catenin regulator adenomatous polyposis coli (APC), leading to downregulation of apoptosis and upregulation of proliferation and metabolism by modulating Wnt/β-catenin pathway in LUAD cells [ 86 ]. However, it is proved that Siah1 interacts, ubiquitinates and degrades 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) through ubiquitin-proteasome pathway, subsequently upregulating cholesterol synthesis, cisplatin sensitivity and downregulating NSCLC tumor development such as proliferation, migration and invasion [ 87 ]. An essential E3 in monomeric RING, praja ring finger ubiquitin ligase 2 (Praja2) can interact with homeobox B9 (HOXB9).…”