The microprotein CASIMO1 interacts with squalene epoxidase modulating lipid droplet formation

2018-06-12 16:23:46 GMT+0800

   Squalene monooxygenase (also called squalene epoxidase) is an enzyme that uses NADPH and molecular oxygen to oxidize squalene to 2,3-oxidosqualene (squalene epoxide). Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. In humans, squalene epoxidase is encoded by the SQLE gene. Squalene monooxygenase (SqMO) was formerly referred to as squalene epoxidase (SqE) in the literature.

   On May 16, 2018, Nature published an article called The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. The article points out that squalene epoxidase (SQLE) as a key enzyme in cholesterol synthesis and a known oncogene in breast cancer knockdown mimicked the Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1, a novel microprotein of 10 kDa), knockdown phenotype and in turn SQLE overexpression fully rescued the effect of CASIMO1 knockdown.

   Breast cancer is a leading cause of cancer-related death in women. CASIMO1 RNA is overexpressed predominantly in hormone receptor-positive breast tumors. Its knockdown leads to decreased proliferation in multiple breast cancer cell lines. Its loss disturbs the organization of the actin cytoskeleton, leads to inhibition of cell motility, and causes a G0/G1 cell cycle arrest. The proliferation phenotype upon overexpression is observed only with CASIMO1 protein expression, but not with a non-translatable mutant attributing the effects to the sORF-derived protein rather than a lncRNA function. CASIMO1 microprotein interacts with squalene epoxidase (SQLE). Overexpression of CASIMO1 leads to SQLE protein accumulation without affecting its RNA levels and increased lipid droplet clustering, while knockdown of CASIMO1 decreased SQLE protein abundance and ERK phosphorylation downstream of SQLE. Importantly, SQLE knockdown mimicked the CASIMO1 knockdown phenotype and in turn SQLE overexpression fully rescued the effect of CASIMO1 knockdown. These findings establish CASIMO1 as the first functional microprotein that plays a role in carcinogenesis and is implicated in the cell lipid homeostasis. Hence, they speculate that the phenotypes observed upon modulation of the CASIMO1 microprotein levels are exerted through its interaction with SQLE protein impacting the cell’s metabolic homeostasis.

Breast cancer related kit:



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