The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation
The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation
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DOI：
10.1038/s41388-018-0281-5
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发表时间：
2018-08-23
期刊：
影响因子：
8
通讯作者：
Diederichs, Sven
中科院分区：
文献类型：
--
作者：
Polycarpou-Schwarz, Maria;Gross, Matthias;Diederichs, Sven
乳腺癌是女性癌症相关死亡的主要原因。小开放阅读框（sORF）编码的蛋白质或微蛋白构成了一类新的分子，通常由假定的长非编码RNA转录物（lncRNA）转录。其中一些sORF的翻译已经得到证实，但它们的细胞功能和重要性在很大程度上仍然未知。在这里，我们报告了一种新的10 kDa的微蛋白，我们命名为癌症相关的小积分膜开放阅读框架1（CASIMO 1）的鉴定和表征。CASIMO 1 RNA主要在激素受体阳性乳腺肿瘤中过表达。它的敲低导致多种乳腺癌细胞系的增殖减少。它的丢失扰乱了肌动蛋白细胞骨架的组织，导致细胞运动的抑制，并导致G（0）/G（1）细胞周期停滞。仅在CASIMO 1蛋白表达的情况下观察到过表达后的增殖表型，但在将效应归因于sORF衍生蛋白而不是lncRNA功能的不可翻译突变体的情况下未观察到。CASIMO 1微蛋白与角鲨烯环氧酶（SQLE）相互作用，SQLE是胆固醇合成的关键酶，也是乳腺癌中的已知癌基因。CASIMO 1的过表达导致SQLE蛋白积累而不影响其RNA水平和增加脂滴聚集，而CASIMO 1的敲低降低SQLE蛋白丰度和SQLE下游的ERK磷酸化。重要的是，SQLE敲低模拟了CASIMO 1敲低表型，反过来SQLE过表达完全挽救了CASIMO 1敲低的效果。这些发现确立了CASIMO 1是第一个在致癌作用中起作用并涉及细胞脂质稳态的功能性微蛋白。
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 G(0)/G(1) 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.z