HuR Controls Glutaminase RNA Metabolism

Authors

Douglas Adamoski
Larissa M Dos Reis
Ana Carolina Paschoalini Mafra
Felipe Corrêa-da-Silva
Pedro Manoel Mendes de Moraes-Vieira
Ioana Berindan-Neagoe
George A Calin
Sandra Martha Gomes Dias

Publication Date

7-4-2024

Journal

Nature Communications

Abstract

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.

Keywords

Glutaminase, ELAV-Like Protein 1, Humans, Breast Neoplasms, Cell Line, Tumor, Female, RNA, Messenger, Gene Expression Regulation, Neoplastic, Alternative Splicing, Cell Proliferation, Glutamine, RNA Stability

Comments

Supplementary Materials

PMID: 38965208