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.

中文翻译：

---

与癌症相关的微蛋白CASIMO1控制细胞增殖，并与角鲨烯环氧酶相互作用，调节脂质滴的形成。

乳腺癌是女性与癌症相关的死亡的主要原因。小型开放阅读框（sORF）编码的蛋白质或微蛋白质构成了一类新的分子，通常从假定的长非编码RNA转录本（lncRNA）转录而来。这些sORF的某些翻译已得到证实，但其细胞功能和重要性仍未知。在这里，我们报告鉴定和表征的一种新的10kDa的微蛋白，我们将其命名为癌症相关的小整体膜开放阅读框1（CASIMO1）。CASIMO1 RNA主要在激素受体阳性的乳腺肿瘤中过表达。它的敲低导致多种乳腺癌细胞系中增殖的减少。它的丢失会破坏肌动蛋白细胞骨架的组织，导致细胞运动受到抑制，并导致G₀ /克₁细胞周期停滞。仅在CASIMO1蛋白表达时观察到过表达时的增殖表型，而在归因于sORF衍生蛋白而不是lncRNA功能的不可翻译突变体中则未观察到。CASIMO1微蛋白与角鲨烯环氧酶（SQLE）相互作用，角鲨烯环氧酶是胆固醇合成中的关键酶，也是乳腺癌中已知的癌基因。CASIMO1的过表达导致SQLE蛋白质积聚而不影响其RNA水平和脂质滴簇的增加，而敲除CASIMO1则降低SQLE蛋白质的丰度和ERK下游的ERK磷酸化。重要的是，SQLE敲除模仿了CASIMO1敲除的表型，SQLE的过表达又完全拯救了CASIMO1敲除的效果。