谷氨酰胺酶 (GLS) 与细胞生长和肿瘤进展直接相关，使其成为癌症治疗的靶点。 RNA 结合蛋白 HuR（由 ELAVL1 基因编码）影响 mRNA 稳定性和选择性剪接。 ELAVL1 过度表达在多种癌症中很常见，包括乳腺癌。在这里，我们证明 HuR 调节乳腺癌中 GLS mRNA 的选择性剪接和异构体翻译/稳定性。 ELAVL1 表达升高与谷氨酰胺酶同工型 C (GAC) 和肾型 (KGA) 水平高相关，这与患者预后不良相关。敲低 ELAVL1 会降低 KGA 并增加 GAC 水平，增强谷氨酰胺回补进入 TCA 循环，并驱动细胞产生谷氨酰胺依赖。此外，我们发现，GLS 的化学抑制与 ELAVL1 沉默相结合可协同减少乳腺癌细胞的生长和侵袭。这些发现表明，GLS 和 HuR 的双重抑制为乳腺癌治疗提供了一种治疗策略。© 2024。作者。

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and drives cells towards glutamine dependence. Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment.© 2024. The Author(s).