Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer

Juan Liu, Cen Zhang, Tianliang Zhang, Chun Yuan Chang, Jianming Wang, Ludvinna Bazile, Lanjing Zhang, Bruce G. Haffty, Wenwei Hu, Zhaohui Feng

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1–GTP, to inhibit Rac1–GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.

Original languageEnglish (US)
Pages (from-to)1830-1846
Number of pages17
JournalNature Metabolism
Volume4
Issue number12
DOIs
StatePublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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