Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer

Jianhui Guo, Li Zheng, Wenyong Liu, Xianshu Wang, Zemin Wang, Zehua Wang, Amy J. French, Dongchon Kang, Lin Chen, Stephen N Thibodeau, Wanguo Liu

Research output: Contribution to journalArticle

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Abstract

The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cellinduced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatelliteunstable CRCs.

Original languageEnglish (US)
Pages (from-to)2978-2987
Number of pages10
JournalCancer Research
Volume71
Issue number8
DOIs
StatePublished - Apr 15 2011

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Mitochondrial DNA
Microsatellite Repeats
Colorectal Neoplasms
Microsatellite Instability
Mutation
Cytochromes b
Cisplatin
Mitochondria
Premature Aging
Neoplasms
Frameshift Mutation
Tumor Cell Line
DNA Replication
Heterografts
Carcinogenesis
Heart Failure
Cell Proliferation
Apoptosis
Cell Line
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer. / Guo, Jianhui; Zheng, Li; Liu, Wenyong; Wang, Xianshu; Wang, Zemin; Wang, Zehua; French, Amy J.; Kang, Dongchon; Chen, Lin; Thibodeau, Stephen N; Liu, Wanguo.

In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 2978-2987.

Research output: Contribution to journalArticle

Guo, Jianhui ; Zheng, Li ; Liu, Wenyong ; Wang, Xianshu ; Wang, Zemin ; Wang, Zehua ; French, Amy J. ; Kang, Dongchon ; Chen, Lin ; Thibodeau, Stephen N ; Liu, Wanguo. / Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer. In: Cancer Research. 2011 ; Vol. 71, No. 8. pp. 2978-2987.
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