Cell Death and Disease (Jul 2024)

MAZ-mediated up-regulation of BCKDK reprograms glucose metabolism and promotes growth by regulating glucose-6-phosphate dehydrogenase stability in triple-negative breast cancer

  • Yan Li,
  • Yuxiang Lin,
  • Yali Tang,
  • Meichen Jiang,
  • Xiaobin Chen,
  • Hanxi Chen,
  • Qian Nie,
  • Jinqiao Wu,
  • Xin Tong,
  • Jing Li,
  • Liuwen Yu,
  • Jialin Hou,
  • Wenhui Guo,
  • Lili Chen,
  • Minyan Chen,
  • Jie Zhang,
  • Shuhai Lin,
  • Fangmeng Fu,
  • Chuan Wang

DOI
https://doi.org/10.1038/s41419-024-06835-y
Journal volume & issue
Vol. 15, no. 7
pp. 1 – 15

Abstract

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Abstract Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming.