Genes and pathways downstream of telomerase in melanoma metastasis

Abstract

Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.differentiation ͉ glycolysis T elomerase is a ribonucleoprotein complex composed of core protein (telomerase reverse transcriptase) and RNA (telomerase RNA or TER) moieties. The most extensively characterized function of telomerase is to maintain the telomeric repeats capping the ends of eukaryotic chromosomes and thereby preserve their integrity by preventing end-to-end fusions (1-4). Whereas normal somatic cells have diminished telomerase activity, Ͼ90% of human cancers overexpress telomerase (5, 6). The well established roles for telomerase in tumor initiation and cellular immortalization (7,8) have led to the identification of telomerase as a potentially important molecular target in cancer therapeutics (9-11). To date, multiple studies have examined the utility of targeting telomerase to inhibit tumor cell proliferation (12-16).Although the importance of telomerase for tumor cell proliferation is well documented, its impact on tumor invasion and metastasis has been studied less. In our recent study, we used a systemic injection model of an effective anti-telomerase ribozyme to reveal that inhibiting telomerase activity in tumorbearing mice significantly reduces metastatic progression (16). Here, we examine the direct role played by telomerase in the metastatic potential of murine melanoma and characterize cellular pathways altered by telomerase suppression in tumor cells. We show that stable, ribozyme-mediated suppression of TER levels in melanoma cells results in a more dendritic phenotype, accompanied by increased tyrosinase expression and pigment production. Furthermore, we show that TER suppression results in down-regulation of glycolytic pathway genes and significantly reduces glucose metabolism, providing a mechanistic basis for the reduced metastatic capacity and increased pigment production observed. ResultsTo directly examine the role of te...

Genetic Variations in TERT-CLPTM1L Genes and Risk of Lung Cancer in a Chinese Population

“…It has been known that telomere is essential for the preservation of chromosomal integrity and stability, cellular immortality and carcinogenesis of various cancers ( Weinrich et al, 1997;Feldser et al, 2003;Rodier et al, 2005). TERT, which regulates activity of telomerase and synthesis of telomere, shows a high-level of expression in many cancers, including lung cancer (Bagheri et al, 2006). Hence, TERT is considered to play a vital role in unlimited cell division and carcinogenesis, especially among Asians (Hanahan et al, 2000;Qi et al, 2012;Zhang et al, 2012).…”

TERT rs2736098 Polymorphism and Cancer Risk: Results of a Meta-analysis

“…Over-expression of the TERT gene and telomerase activity has been recognized in many types of cancers, and can possibly lead to unlimited cell division and carcinogenesis (Liu et al, 2010). In addition, telomerase may play a role in tumor progression and metastasis by activation of the glycolytic pathway and in suppression of tumor cell differentiation (Nosrati et al, 2004;Bagheri et al, 2006;Liu et al, 2010). The role of TERT rs2736098 expression has been well documented in the tumorigenesis of various cancers (Savage et al, 2007;Jin et al, 2009;Rafnar et al, 2009;Liu et al, 2010;Chen et al, 2011;Gago-Dominguez et al, 2011), but the influence of the TERT rs2736098 polymorphism in the development of cancer has been evaluated by only a few meta-analysis studies..…”

TERT promoter mutations in melanoma survival

“…43 Conversely, suppression of telomerase activity had shown to significantly reduce tumor invasion and metastatic potential in a melanoma mouse model. 44 From those observations it can be hypothesized that increased TERT expression as a consequence of mutations may play a role in tumor growth, which is supported by the association of TERT promoter mutations with markers of adverse outcomes in melanoma and many other cancers. In melanoma, as shown previously, those mutations associated with increased tumor thickness, presence of ulceration, vertical growth and regional/distant metastases.…”