Suppressor genes of lung cancer
Abstracts
Initial Award Abstract |
|
Lung cancer is one of the most common diseases of Americans. Tobacco smoking is the best known risk factor for lung cancer. Although how smoking causes lung cancer is not entirely clear, it is likely that smoking related cancer causing compounds may directly lead to changes (mutations) in cellular genes. The normal function of some genes is to prevent the development of cancer. These genes are called tumor suppressor genes. Mutations in these genes can lead to their inability to carry out their normal function. A large body of evidence shows that loss of function of the retinoblastoma gene (Rb) plays an important role in lung cancer development. The Rb protein functions to inhibit cell growth. It does so by binding to several other proteins. The RIZ1 protein is one such protein. We have generated preliminary results which suggest a role for RIZ1 as a tumor suppressor involved in Rb function. The RIZ1 protein is found in many normal tissues but is frequently lost in many cancer cell lines and tissues. The long term goal of this proposal is to address the tumor suppressor functions of RIZ1 and Rb in lung cancer. Specifically, we will address: 1) Is RIZ1 gene expression altered in lung cancer? 2) Can RIZ1 suppress growth of lung cancer cells? 3) Is RIZ1 a key element of the Rb tumor suppression pathway? We hope that our research will lead to the identification of a novel tumor suppressor and also a deeper understanding of the Rb tumor suppression pathway in lung cancer development. Such knowledge can be directly exploited for gene therapy of lung cancer. |
Final Report |
|
Diet and smoking are the two major causes of human cancers in the United States, each accounts for ~33% of cancer death. Lung cancer is strongly linked to smoking and abnormal diet, but the mechanisms remain to be established. Inactivation of tumor suppressor genes such as Rb and p53 has been established to play an important role in cancer formation. The RIZ1 gene was isolated based on its ability to bind to the Rb protein. RIZ1 has since been found to be a tumor suppressor belonging to a superfamily of protein/histone methyltransferases. The finding of tumor suppressor function among methyltransferases may significantly advance our understanding of the mechanisms of the diet-cancer relationship.
Significant results from this grant period are the following. RIZ1 was found commonly silenced in lung cancer cell lines. A strong correlation is found between DNA methylation and loss of RIZ1 expression. Consistent with a tumor suppressor role in lung cancer, RIZ1 caused G2/M arrest when it was over expressed in lung cancer cell lines. We also found that the increased RIZ1 protein level in the presence of Rb is correlated with increased mRNA levels. In studying RIZ-Rb interaction, we found that loss of RIZ1 did not rescue the embryo lethality phenotype of Rb mutant mice. Finally, we found that RIZ1 has the suspected protein methyltransferase activities. We further proposed the hypotheisis that protein methyltransferases of the RIZ1 class represent a super family of tumor suppressor genes. These enzymes may directly contribute to cancer formation caused by dietary nutrient imbalance. The typical western diet, which is high in meat and low in vegetables, are deficient in methyl donor nutrients (folate, vitamin B12 and B6) and is a major risk factor of lung cancer. Our future research goal is to further establish the hypothesis that diet nutrient imbalance causes cancer by directly inactivating the enzyme activity of the protein methyltransferase class of tumor suppressor genes. This will have great impact in lung cancer prevention. |
Publications
| RIZ1 , but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer and forced RIZ1 expression causes G2/M cell cycle arrest and/or apoptosis |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: He L, Yu J, Liu X, et al |
ART |
| Yr: 1999 |
Vol: 58 |
Nbr: |
Abs: |
Pg: 4238-4244 |
| The yin-yang of PR domain family genes in tumorigenesis |
| Periodical: Histopathology |
Index Medicus: |
| Authors: Jiang G-L, Huang S |
ART |
| Yr: 2000 |
Vol: 15 |
Nbr: |
Abs: |
Pg: 109-117 |
| Decreased RIZ1 expression but not RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1 |
| Periodical: International Journal of Cancer |
Index Medicus: |
| Authors: Jiang G-L, Liu L, Buyse I, Simon D, Huang S |
ART |
| Yr: 1999 |
Vol: 83 |
Nbr: |
Abs: |
Pg: 541-547 |
| PFM1 (PRDM4), a new member of the PR domain family, maps to a tumor suppressor locus on human chromosome 12q23-q24.1 |
| Periodical: Genomics |
Index Medicus: |
| Authors: Yang X-H, Huang S |
ART |
| Yr: 1999 |
Vol: 61 |
Nbr: |
Abs: |
Pg: 319-325 |
| Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13-p36.23 and mutational analysis of the RIZ gene localized to the region |
| Periodical: Genes Chromosomes Cancer |
Index Medicus: |
| Authors: Fang W, Piao Z, Simon D, Sheu J-C, Huang S |
ART |
| Yr: 2000 |
Vol: 28 |
Nbr: |
Abs: |
Pg: 269-275 |
| Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis |
| Periodical: Proceedings of the National Academy of Sciences of the United States of America |
Index Medicus: |
| Authors: Chadwick RB, Jiang G-L, Bennington GA, et al |
ART |
| Yr: 2000 |
Vol: 97 |
Nbr: |
Abs: |
Pg: 2662-2667 |
| Chromatin becomes hot in cancer pathogenesis and therapy |
| Periodical: Trends in Genetics |
Index Medicus: |
| Authors: Huang S |
ART |
| Yr: 2000 |
Vol: 16 |
Nbr: |
Abs: |
Pg: 200-201 |
| RIZ1 is a tumor suppressor on chromosome band 1p36, a commonly deleted region in human cancers |
| Periodical: Nature Medicine |
Index Medicus: |
| Authors: Steele-Perkins G, Jiang G-L, Fang W, et al |
ART |
| Yr: 2000 |
Vol: |
Nbr: |
Abs: |
Pg: |
| Involvement of the MKK6-p38 cascade in radiation-induced cell cycle arrest |
| Periodical: Molecular and Cellular Biology |
Index Medicus: |
| Authors: Wang X, McGowan CH, Zhao M, et al |
ART |
| Yr: 2000 |
Vol: 20 |
Nbr: |
Abs: |
Pg: 4543-4552 |
| Frequent frameshift mutations of RIZ in human gastrointestinal and endometrial carcinomas with microsatellite instability |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Piao Z, Fang W, Malkhosyan S, et al |
ART |
| Yr: 2000 |
Vol: 6 |
Nbr: |
Abs: |
Pg: 4701-4704 |
| RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum |
| Periodical: Genes Chromosomes Cancer |
Index Medicus: |
| Authors: Sakurada K, Furukawa T, Kato Y, Kayama T, Huang S, Horii A |
ART |
| Yr: 2001 |
Vol: 30 |
Nbr: |
Abs: |
Pg: 207-211 |
| Preferential loss in human cancer of a polymorphic RIZ allele that is more common in Asians than Caucasians |
| Periodical: British Journal of Cancer |
Index Medicus: |
| Authors: Fang W, Piao Z, Simon D, Sheu J-C, Perucho M, Huang S |
ART |
| Yr: 2001 |
Vol: 84 |
Nbr: |
Abs: |
Pg: 743-747 |
| Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Jiang G-L, Huang S |
ART |
| Yr: 2001 |
Vol: 61 |
Nbr: |
Abs: |
Pg: 1796-1798 |
| Tumor formation and inactivation of RIZ1, a Rb-binding member of a nuclear protein methyltransferase superfamily |
| Periodical: Genes and Development |
Index Medicus: |
| Authors: Steele-Perkins G, Fang W, Van Gele M, et al |
ART |
| Yr: 2001 |
Vol: 15 |
Nbr: |
Abs: |
Pg: 2250-2262 |
| The PR domain of the rb-binding zinc finger gene R1Z1 is a protein-binding interface and is related to the SET domain functioning in chromatin mediated gene expression. |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Huang S, Shao G, and Liu L |
ART |
| Yr: 1998 |
Vol: 273 |
Nbr: |
Abs: |
Pg: 15933 - 15940 |
| The retinoblastoma-protein interacting zinc finger gene RIZ in lp36-linked cancers. |
| Periodical: Frontiers in Bioscience |
Index Medicus: |
| Authors: Huang S |
ART |
| Yr: 1999 |
Vol: 4 |
Nbr: |
Abs: |
Pg: D528 - D532 |
| Hypermethylation in human cancers of the R1Z1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Du Y, Carling T, Fang W, Piao Z, Sheu J-C, and Huang S |
ART |
| Yr: 2001 |
Vol: 22 |
Nbr: |
Abs: |
Pg: 8094 - 8099 |
| The tumor suppressor gene RIZ in cancer gene therapy. |
| Periodical: Oncology Reports |
Index Medicus: |
| Authors: Canote R, Du Y, Carling T, Tian F, Peng Z and Huang S |
ART |
| Yr: 2002 |
Vol: 9 |
Nbr: |
Abs: |
Pg: 57 - 60 |
| Histone methyltransferases, diet nutrients and tumor suppressors. |
| Periodical: Nature Reviews. Cancer |
Index Medicus: |
| Authors: Huang S |
ART |
| Yr: 2002 |
Vol: 2 |
Nbr: |
Abs: |
Pg: 469 - 476 |
| RIZ1 , but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer and forced RIZ1 expression causes G2/M cell cycle arrest and/or apoptosis |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: He L, Yu J, Liu X, et al |
ART |
| Yr: 1999 |
Vol: 58 |
Nbr: |
Abs: |
Pg: 4238-4244 |
| The yin-yang of PR domain family genes in tumorigenesis |
| Periodical: Histopathology |
Index Medicus: |
| Authors: Jiang G-L, Huang S |
ART |
| Yr: 2000 |
Vol: 15 |
Nbr: |
Abs: |
Pg: 109-117 |
| Decreased RIZ1 expression but not RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1 |
| Periodical: International Journal of Cancer |
Index Medicus: |
| Authors: Jiang G-L, Liu L, Buyse I, Simon D, Huang S |
ART |
| Yr: 1999 |
Vol: 83 |
Nbr: |
Abs: |
Pg: 541-547 |
| PFM1 (PRDM4), a new member of the PR domain family, maps to a tumor suppressor locus on human chromosome 12q23-q24.1 |
| Periodical: Genomics |
Index Medicus: |
| Authors: Yang X-H, Huang S |
ART |
| Yr: 1999 |
Vol: 61 |
Nbr: |
Abs: |
Pg: 319-325 |
| Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13-p36.23 and mutational analysis of the RIZ gene localized to the region |
| Periodical: Genes Chromosomes Cancer |
Index Medicus: |
| Authors: Fang W, Piao Z, Simon D, Sheu J-C, Huang S |
ART |
| Yr: 2000 |
Vol: 28 |
Nbr: |
Abs: |
Pg: 269-275 |
| Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis |
| Periodical: Proceedings of the National Academy of Sciences of the United States of America |
Index Medicus: |
| Authors: Chadwick RB, Jiang G-L, Bennington GA, et al |
ART |
| Yr: 2000 |
Vol: 97 |
Nbr: |
Abs: |
Pg: 2662-2667 |
| Chromatin becomes hot in cancer pathogenesis and therapy |
| Periodical: Trends in Genetics |
Index Medicus: |
| Authors: Huang S |
ART |
| Yr: 2000 |
Vol: 16 |
Nbr: |
Abs: |
Pg: 200-201 |
| RIZ1 is a tumor suppressor on chromosome band 1p36, a commonly deleted region in human cancers |
| Periodical: Nature Medicine |
Index Medicus: |
| Authors: Steele-Perkins G, Jiang G-L, Fang W, et al |
ART |
| Yr: 2000 |
Vol: |
Nbr: |
Abs: |
Pg: |
| Involvement of the MKK6-p38 cascade in radiation-induced cell cycle arrest |
| Periodical: Molecular and Cellular Biology |
Index Medicus: |
| Authors: Wang X, McGowan CH, Zhao M, et al |
ART |
| Yr: 2000 |
Vol: 20 |
Nbr: |
Abs: |
Pg: 4543-4552 |
| Frequent frameshift mutations of RIZ in human gastrointestinal and endometrial carcinomas with microsatellite instability |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Piao Z, Fang W, Malkhosyan S, et al |
ART |
| Yr: 2000 |
Vol: 6 |
Nbr: |
Abs: |
Pg: 4701-4704 |
| RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum |
| Periodical: Genes Chromosomes Cancer |
Index Medicus: |
| Authors: Sakurada K, Furukawa T, Kato Y, Kayama T, Huang S, Horii A |
ART |
| Yr: 2001 |
Vol: 30 |
Nbr: |
Abs: |
Pg: 207-211 |
| Preferential loss in human cancer of a polymorphic RIZ allele that is more common in Asians than Caucasians |
| Periodical: British Journal of Cancer |
Index Medicus: |
| Authors: Fang W, Piao Z, Simon D, Sheu J-C, Perucho M, Huang S |
ART |
| Yr: 2001 |
Vol: 84 |
Nbr: |
Abs: |
Pg: 743-747 |
| Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Jiang G-L, Huang S |
ART |
| Yr: 2001 |
Vol: 61 |
Nbr: |
Abs: |
Pg: 1796-1798 |
| Tumor formation and inactivation of RIZ1, a Rb-binding member of a nuclear protein methyltransferase superfamily |
| Periodical: Genes and Development |
Index Medicus: |
| Authors: Steele-Perkins G, Fang W, Van Gele M, et al |
ART |
| Yr: 2001 |
Vol: 15 |
Nbr: |
Abs: |
Pg: 2250-2262 |
| The PR domain of the rb-binding zinc finger gene R1Z1 is a protein-binding interface and is related to the SET domain functioning in chromatin mediated gene expression. |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Huang S, Shao G, and Liu L |
ART |
| Yr: 1998 |
Vol: 273 |
Nbr: |
Abs: |
Pg: 15933 - 15940 |
| The retinoblastoma-protein interacting zinc finger gene RIZ in lp36-linked cancers. |
| Periodical: Frontiers in Bioscience |
Index Medicus: |
| Authors: Huang S |
ART |
| Yr: 1999 |
Vol: 4 |
Nbr: |
Abs: |
Pg: D528 - D532 |
| Hypermethylation in human cancers of the R1Z1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Du Y, Carling T, Fang W, Piao Z, Sheu J-C, and Huang S |
ART |
| Yr: 2001 |
Vol: 22 |
Nbr: |
Abs: |
Pg: 8094 - 8099 |
| The tumor suppressor gene RIZ in cancer gene therapy. |
| Periodical: Oncology Reports |
Index Medicus: |
| Authors: Canote R, Du Y, Carling T, Tian F, Peng Z and Huang S |
ART |
| Yr: 2002 |
Vol: 9 |
Nbr: |
Abs: |
Pg: 57 - 60 |
| Histone methyltransferases, diet nutrients and tumor suppressors. |
| Periodical: Nature Reviews. Cancer |
Index Medicus: |
| Authors: Huang S |
ART |
| Yr: 2002 |
Vol: 2 |
Nbr: |
Abs: |
Pg: 469 - 476 |
