TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. (22nd April 2022)

• Record Type: Journal Article
• Authors: Huang, Qichao; Wu, Dan; Zhao, Jing; Yan, Zeyu; Chen, Lin; Guo, Shanshan; Wang, Dalin; Yuan, Chong; Wang, Yinping; Liu, Xiaoli; Xing, Jinliang
• Is Part Of: EMBO journal. Volume 41:Number 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-04-22
• Subjects: HCC -- metastasis -- mitochondrial transcription factor A -- nuclear F‐actin; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021110324
• Languages: English
• ISSNs: 0261-4189

Abstract

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. SYNOPSIS: Mitochondrial metabolic alterations have been linked to tumor metastasis, but the mechanisms are poorly understood. Here, the loss of mitochondrial transcription factor A (TFAM) was identified as a key factor for nuclear actin polymerization and HCC metastasis. TFAM loss induced rapid spontaneous lung metastasis in mouse liver cancer models. The polymerization of nuclear actin induced by TFAM knockdown was causally linked to the high metastatic ability of HCC cells. Downregulated TFAM induced malonylation of mDia2 to promote its nuclear translocation and nuclear actin polymerization. Down‐regulation of TFAM was associated with poor prognosis in HCC patient. Abstract : Loss of function of the Mitochondrial Transcription Factor A promotes liver cancer progression through malonylation of the formin mDia2, its nuclear translocation and the polymerisation of nuclear actin for chromatin regulation.