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A Fluorescence-based Assay for Characterization and Quantification of Lipid Droplet Formation in Human Intestinal Organoids
Published on: October 13, 2019
The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase
Maria Polycarpou-Schwarz1,2, Matthias Groß1,2, Pieter Mestdagh3
1Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
Breast cancer is a leading cause of cancer-related death in women. Small open reading frame (sORF)-encoded proteins or microproteins constitute a new class of molecules often transcribed from presumed long non-coding RNA transcripts (lncRNAs). The translation of some of these sORFs has been confirmed, but their cellular function and importance remains largely unknown. Here, we report the identification and characterization of a novel microprotein of 10 kDa, which we named Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1). 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), a key enzyme in cholesterol synthesis and a known oncogene in breast cancer. 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.
Insights
We identified a new microprotein, Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1), overexpressed in breast tumors. CASIMO1 impacts cell proliferation, motility, and lipid homeostasis by interacting with squalene epoxidase (SQLE).
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Breast cancer remains a significant cause of mortality in women.
- Small open reading frame (sORF)-encoded proteins (microproteins) are a newly identified class of molecules with largely unknown functions.
- Long non-coding RNAs (lncRNAs) are often implicated in gene regulation, but can also encode microproteins.
Purpose of the Study:
- To identify and characterize novel microproteins involved in breast cancer.
- To elucidate the function of the newly identified microprotein, CASIMO1, in breast cancer cell behavior.
- To investigate the molecular mechanisms underlying CASIMO1's role in carcinogenesis and lipid homeostasis.
Main Methods:
- Identification and characterization of a novel 10 kDa microprotein, CASIMO1.
- Analysis of CASIMO1 RNA and protein expression in breast cancer cell lines and tumors.
- Functional studies including knockdown and overexpression of CASIMO1 and its mutants.
- Investigation of CASIMO1's interaction with squalene epoxidase (SQLE) and its downstream effects.
- Assessment of effects on cell proliferation, actin cytoskeleton organization, cell motility, cell cycle, and lipid droplet clustering.
Main Results:
- CASIMO1 RNA is overexpressed in hormone receptor-positive breast tumors.
- CASIMO1 knockdown decreased proliferation, disturbed actin cytoskeleton, inhibited motility, and caused G0/G1 cell cycle arrest.
- CASIMO1 protein, not its RNA, mediated these effects.
- CASIMO1 interacts with SQLE, leading to SQLE protein accumulation, increased lipid droplet clustering, and altered ERK phosphorylation.
- SQLE knockdown mimicked CASIMO1 knockdown, and SQLE overexpression rescued CASIMO1 knockdown phenotypes.
Conclusions:
- CASIMO1 is the first functional microprotein identified to play a role in breast cancer development.
- CASIMO1 influences cell proliferation, motility, and cytoskeleton organization.
- CASIMO1 regulates cell lipid homeostasis through interaction with and stabilization of SQLE protein.
- CASIMO1 represents a potential novel therapeutic target in breast cancer treatment.
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