Frequent Truncating Mutation of TFAM Induces Mitochondrial DNA Depletion and Apoptotic Resistance in Microsatellite-Unstable Colorectal Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8; pp. 2978 - 2987
• Main Authors: JIANHUI GUO, LI ZHENG, WANGUO LIU, WENYONG LIU, XIANSHU WANG, ZEMIN WANG, ZEHUA WANG, FRENCH, Amy J, KANG, Dongchon, LIN CHEN, THIBODEAU, Stephen N
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.2011
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Base Sequence; Biological and medical sciences; Cell Line, Tumor; Cisplatin - pharmacology; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytochromes b - genetics; Cytochromes b - metabolism; DNA, Mitochondrial - genetics; DNA-Binding Proteins - genetics; Down-Regulation; Frameshift Mutation; Gastroenterology. Liver. Pancreas. Abdomen; HCT116 Cells; Humans; Medical sciences; Mice; Mice, Nude; Microsatellite Instability; Mitochondrial Proteins - genetics; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription Factors - genetics; Transcription, Genetic; Transplantation, Heterologous; Tumors; Rectal disease; Colorectal cancer; Mitochondrial DNA; Malignant tumor; Colonic disease; Resistance; Depletion; Microsatellite DNA; Digestive diseases; Intestinal disease; Frequency; Genetics; Instability; Mutation; Cancer; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-3482

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.