Krüppel-like factor 4 (KLF4) induces mitochondrial fusion and increases spare respiratory capacity of human glioblastoma cells

Shuyan Wang, Xiaohai Shi, Shuang Wei, Ding Ma, Olutobi Oyinlade, Sheng Qing Lv, Mingyao Ying, Yu Alex Zhang, Steven Michael Claypool, Paul Watkins, Shuli Xia

Research output: Contribution to journalArticlepeer-review

Abstract

Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor critical for the regulation of many cellular functions in both normal and neoplastic cells. Here, using human glioblastoma cells, we investigated KLF4’s effects on cancer cell metabolism. We found that forced KLF4 expression promotes mitochondrial fusion and induces dramatic changes in mitochondrial morphology. To determine the impact of these changes on the cellular functions following, we analyzed how KLF4 alters glioblastoma cell metabolism, including glucose uptake, glycolysis, pentose phosphate pathway, and oxidative phosphorylation. We did not identify significant differences in baseline cellular metabolism between control and KLF4-expressing cells. However, when mitochondrial function was impaired, KLF4 significantly increased spare respiratory capacity and levels of reactive oxygen species in the cells. To identify the biological effects of these changes, we analyzed proliferation and survival of control and KLF4-expressing cells under stress conditions, including serum and nutrition deprivation. We found that following serum starvation, KLF4 altered cell cycle progression by arresting the cells at the G2/M phase and that KLF4 protected cells from nutrition deprivation–induced death. Finally, we demonstrated that methylation-dependent KLF4-binding activity mediates mitochondrial fusion. Specifically, the downstream targets of KLF4-mCpG binding, guanine nucleotide exchange factors, serve as the effector of KLF4-induced mitochondrial fusion, cell cycle arrest, and cell protection. Our experimental system provides a robust model for studying the interactions between mitochondrial morphology and function, mitochondrial dynamics and metabolism, and mitochondrial fusion and cell death during tumor initiation and progression.

Original languageEnglish (US)
Pages (from-to)6544-6555
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number17
DOIs
StatePublished - Apr 27 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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