1. Academic Validation
  2. TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis

  • EMBO J. 2022 Jun 1;41(11):e110324. doi: 10.15252/embj.2021110324.
Qichao Huang  # 1 Dan Wu  # 1 Jing Zhao  # 1 Zeyu Yan 2 Lin Chen 1 Shanshan Guo 1 Dalin Wang 3 Chong Yuan 1 Yinping Wang 1 Xiaoli Liu 1 Jinliang Xing 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.
  • 2 Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
  • 3 Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • # Contributed equally.
Abstract

The mechanisms underlying Cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver Cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when Cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human Cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

Keywords

HCC; metastasis; mitochondrial transcription factor A; nuclear F-actin.

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