© The Author 2006. Published by Oxford University Press.
EDITORIAL |
Methylation of Stat1 Promoter Can Contribute to Squamous Cell Carcinogenesis
Affiliation of authors: Division of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA
Correspondence to: Hua Yu, PhD, Division of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA 91010 (e-mail: hyu{at}coh.org).
One of the most recently recognized signaling pathways that regulate tumor cell proliferation and survival involves signal transducers and activators of transcription (STAT) proteins. The STAT family of proteins has seven known members: Stat1, 2, 3, 4, 5A, 5B, and 6. Interestingly, it has become evident that different STAT proteins can serve either tumor suppressing or oncogenic roles. Stat1, for example, functions as a tumor suppressor in several capacities (1–5), whereas Stat3 and to a lesser extent, Stat5, play a critical role in malignant progression at multiple levels (6–9). Although it has been demonstrated that interferon-induced Stat1 activity can cause growth arrest and can induce apoptosis, it is not clear whether a lack of Stat1 in human cancer directly contributes to cancer cell proliferation and survival. If so, what keeps Stat1 from functioning in this manner in tumor cells also remains largely unknown. The article by Xi et al. (10) in this issue of the Journal presents evidence that Stat1 expression in squamous cell carcinoma of the head and neck (SCCHN) is lower than that of normal tissues from individuals without cancer. Restoring Stat1 expression in the tumor cells leads to growth inhibition in vitro and in xenograft tumors, which is accompanied by an increase in p21 expression. Their work further demonstrates that the low expression of Stat1 in SCCHN tumors is associated with Stat1 promoter methylation and that treatment with a methylation inhibitor increases STAT1 and p21 expression and sensitizes SCCHN tumor cells to cisplatin. These findings are novel in several respects.
Many independent studies, which involve mainly mouse tumor models or cell lines, have suggested that Stat1 can function as a tumor suppressor (1–5). How does Stat1 function as a tumor suppressor? Stat1's ability to mediate host immune defenses against tumors has been elegantly demonstrated in mice (2). Increasing Stat1 activity by interferon treatment also leads to cell growth inhibition, which can be explained by Stat1's capacity to induce p21waf and caspase expression (1,5). Moreover, Stat1-deficient cells have defects both in S-phase and G2–M checkpoints in response to DNA damage (11). Also, Stat1- and p53-null mice show more frequent and rapid tumor development than wild-type mice. The basal expression level of the p53 inhibitor Mdm2 is higher in Stat1–/– cells than in wild-type cells, suggesting that Stat1 is a negative regulator of Mdm2 expression (12). The findings by Xi et al. provide direct evidence supporting the notion that the inhibition of Stat1 expression in human cancer may confer a growth and survival advantage.
This study by Xi et al. also suggests that the roles of STATs in cancer involve not only activation of prooncogenic Stat3 and Stat5 but also lack of function of tumor-suppressing Stat1. In normal cells, STAT proteins transmit cytoplasmic signals from polypeptide cytokines and growth factors that bind receptors with intrinsic or associated tyrosine kinase activity (3,8). Activation of STAT proteins by tyrosine phosphorylation in normal cells is transient and rapid. In sharp contrast to this fact, because tyrosine kinases are among the most frequently activated oncogenic proteins in cancers, Stat3—and to a lesser extent, Stat5—are constitutively activated at very high frequency (50%–90%) in many cancers of diverse origin (6–9). Activation of Stat3 in SCCHN has been extensively characterized, and the need for constitutively activated Stat3 signaling for tumor cell survival and proliferation has been demonstrated (6,9). The present study points to coordinate STAT dysregulation in cancer. In this context, there is compelling evidence that Stat3 activation is much stronger and more prolonged in Stat1-null mouse embryo fibroblasts than in wild-type cells. Conversely, elevated Stat1 activity is observed in cells that lack the Stat3 alleles and in cells with constitutively activated Stat3 that are treated with Stat3 antagonists (13,14). Because Stat1 and Stat3 have opposing biologic effects (15), lack of Stat1 expression and function in tumor cells may enhance the activity of Stat3, thereby promoting malignant progression.
The importance of DNA methylation in tumorigenesis has been demonstrated in cancer cells that harbor global genomic DNA hypomethylation and regional hypermethylation at CpG islands of tumor suppressor genes (16). This CpG promoter hypermethylation can silence expression of the associated gene and thus provide cancer cell with a growth advantage similar to deletions or mutations. For example, aberrant methylation of the retinoblastoma (pRb) gene and the von Hippel Lindau (VHL) gene has been demonstrated in retinoblastoma and renal carcinomas, respectively (17,18). Also, methylation-associated silencing can occur at genes involved in hormonal and cytokine signaling pathways, including hormone receptors and the suppressor of cytokine signaling family of proteins (19). Also, it has been found in several tumors that tumor suppressor genes are inactivated by hypermethylation of genes encoding their regulators (20). However, to date, regulation of Stat1 has been linked mostly to protein tyrosine phosphorylation. The present study by Xi et al. reveals a novel regulatory mechanism for Stat1 in cancer. Their data show that the Stat1 promoter is hypermethylated in SCCHN tissues and cell lines and that demethylation of the Stat1 promoter can sensitize tumor cells to chemotherapeutic agent–induced apoptosis. Although further studies are necessary to identify the regulatory mechanisms involved in methylation of the Stat1 promoter in cancer, the findings of Xi et al. indicate that Stat1 is a tumor suppressor in SCCHN and that demethylation may be a potential therapeutic strategy to restore Stat1's tumor suppressive functions.
REFERENCES
(1) Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21WAF1/CIP1 mediated by STAT1. Science 1996;272:719–22.[Abstract]
(2) Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 1998;95:7556–61.
(3) Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell JE Jr. Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc Natl Acad Sci U S A 1996;93:7673–8.
(4) Huang S, Bucana CD, Arsdall MV, Fidler IJ. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene 2002;21:2504–12.[CrossRef][ISI][Medline]
(5) Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol 1997;17:5328–37.[Abstract]
(6) Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS, et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Invest 1998;102:1385–92.[ISI][Medline]
(7) Xi S, Zhang Q, Gooding WE, Smithgall TE, Grandis JR. Constitutive activation of Stat5b contributes to carcinogenesis in vivo. Cancer Res 2003;63:6763–71.
(8) Yu H, Jove R. The STATs of cancer-new molecular targets come of age. Nat Rev Cancer 2004;4:97–105.[ISI][Medline]
(9) Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, et al. Constitutive activation of stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A 2000;97:4227–32.
(10) Xi S, Dyer KF, Kimak M, Zhang Q, Gooding WE, Chaillet JR, et al. Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis. J Natl Cancer Inst 2006;98:181–9.
(11) Townsend PA, Cragg MS, Davidson SM, McCormick J, Barry S, Lawrence KM, et al. STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage. J Cell Sci 2005;118:1629–39.
(12) Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, Stephanou A. STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J Biol Chem 2004;279:5811–20.
(13) Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 1999;10:39–49.[CrossRef][ISI][Medline]
(14) Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibition of Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 2005;11:1314–21.[CrossRef][ISI][Medline]
(15) Shen Y, Devgan G, Darnell JE Jr, Bromberg JF. Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1. Proc Natl Acad Sci U S A 2001;98:1543–8.
(16) Robertson KD. DNA methylation, methyltransferase, and cancer. Oncogene 2001;20:3139–55.[CrossRef][ISI][Medline]
(17) Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 1989;83:155–8.[CrossRef][ISI][Medline]
(18) Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 1994;91:9700–4.
(19) Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG. SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood 2003;101:2784–8.
(20) Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol 2005;45:629–56.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||