HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple-negative breast cancer.

Molecular Oncology
Xin GuoHong-Jiang Wang

Abstract

Dependence on glutamine and acceleration of fatty acid oxidation (FAO) are both metabolic characteristics of triple-negative breast cancer (TNBC). With the rapid growth of tumors, accelerated glutamine catabolism depletes local glutamine, resulting in glutamine deficiency. Studies have shown that the use of alternative energy sources, such as fatty acids, enables tumor cells to continue to proliferate rapidly in a glutamine-deficient microenvironment. However, the detailed mechanisms behind this metabolic change are still unclear. Herein, we identified HRD1 as a regulatory protein for FAO that specifically inhibits TNBC cell proliferation under glutamine-deficient conditions. Furthermore, we observed that HRD1 expression is significantly downregulated under glutamine deprivation and HRD1 directly ubiquitinates and stabilizes CPT2 through K48-linked ubiquitination. In addition, the inhibition of CPT2 expression dramatically suppresses TNBC cell proliferation mediated by HRD1 knockdown in vitro and in vivo. Finally, we found that the glutaminase inhibitor CB839 significantly inhibited TNBC cell tumor growth, but not in the HRD1 knock-downed TNBC cells. These findings provide an invaluable insight into HRD1 as a regulator of lipid...Continue Reading

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Citations

Sep 26, 2021·Virchows Archiv : an International Journal of Pathology·Meng ZhouZe-Fang Ren

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Methods Mentioned

BETA
ubiquitination
pulldown
immunoprecipitation
PCR
xenograft
dissection
coimmunoprecipitation
transfection

Software Mentioned

spss
imagej

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