title: Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer.
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 cell-induced 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 microsatellite-unstable CRCs.
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Guo
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Wenyong
authors.initials: W
authors.lastname: Liu
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Zemin
authors.initials: Z
authors.lastname: Wang
authors.forename: Zehua
authors.initials: Z
authors.lastname: Wang
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Dongchon
authors.initials: D
authors.lastname: Kang
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Wanguo
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045303:Cytochromes b / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D016368:Frameshift Mutation; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053842:Microsatellite Instability; D024101:Mitochondrial Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; D014157:Transcription Factors; D045303:Cytochromes b; D002945:Cisplatin