Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer

Abstract

Background Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC). Methods TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)‐specific TFAM‐knockout mice (TFAM△IEC) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis. Results The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin‐6 in a signal transducer and activator of transcription 3 (STAT3)/miR‐23b‐dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis‐associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β‐catenin induced the upregulation of TFAM through c‐Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity. Conclusions TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.

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

“…TFAM is necessary for transcription and replication of mtDNA, which encodes proteins involved in electron transport chain (ETC), whose defects always induce extensive metabolic changes in TCA cycle. Previously, we found that TFAM plays a crucial regulatory role in mitochondrial energy metabolism in tumor cells (Huang et al , 2014; Wen et al , 2019; Yang et al , 2021). In addition, previous studies have also reported the role of TFAM deficiency in disturbing TCA cycle.…”

“…Interestingly, only TFAM LKO mice rapidly and stably developed lung metastases, suggesting that mitochondrial dysfunction induced by TFAM loss, but not by deregulation of mitochondrial morphology, has a strong ability to drive tumor metastasis. As the key regulator of mtDNA replication and transcription, TFAM has been reported to be deeply involved in metabolic reprogramming and proliferation of tumor cells (Woo et al , 2012; Huang et al , 2014; Yang et al , 2021). Moreover, TFAM expression is a prognostic factor for survival in endometrial carcinomas and colorectal cancer patients with tumor metastasis (Toki et al , 2010; Yoshida et al , 2011).…”

“…Lentiviruses for TFAM, MFN2 knockdown and TFAM, SIRT5 overexpression were prepared as previously reported (Yang et al , 2021). Plasmids encoding nuclear‐located WT actin (Cat.…”

LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis

“…Mitochondria are integral in tumorigenesis given that multiple aspects of mitochondrial functions, including metabolism, oxidative stress regulation, cell death susceptibility and signaling, are involved in tumorigenesis [ 9 , 43 ]. Accumulating evidence indicates that PPR proteins can play an important role in mitochondria [ 12 ].…”

An integrated bioinformatic investigation of mitochondrial energy metabolism genes in colon adenocarcinoma followed by preliminary validation of CPT2 in tumor immune infiltration

“…The mitochondria provide most of the biological energy for the activities of organisms and are important production sites of catabolism of organisms, as well as key regulatory factors of cell proliferation and apoptosis ( 8 ). Mitochondrial dysfunction is closely related to many congenital diseases, inflammation, and tumors ( 9 , 10 ). In tumors, mitochondria are key factors in tumor progression.…”