HuR controls glutaminase RNA metabolism

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 and Sandra Martha Gomes Dias ()
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Douglas Adamoski: Brazilian Center for Research in Energy and Materials (CNPEM)
Larissa M. dos Reis: Brazilian Center for Research in Energy and Materials (CNPEM)
Ana Carolina Paschoalini Mafra: Brazilian Center for Research in Energy and Materials (CNPEM)
Felipe Corrêa-da-Silva: Institute of Biology University of Campinas (UNICAMP)
Pedro Manoel Mendes de Moraes-Vieira: University of Campinas-UNICAMP
Ioana Berindan-Neagoe: University of Medicine and Pharmacy “Iuliu-Hatieganu”
George A. Calin: The University of Texas MD Anderson Cancer Center
Sandra Martha Gomes Dias: Brazilian Center for Research in Energy and Materials (CNPEM)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49874-x

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