RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation
It is well known that RB functions are regulated by posttranslational modifications such as phosphorylation and acetylation, but the significance of lysine methylation on RB has not been fully elucidated. Our expression analysis of SMYD2 by quantitative real-time polymerase chain reaction showed tha...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-06-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612801035 |
| _version_ | 1831727666156273664 |
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| author | Hyun-Soo Cho Shinya Hayami Gouji Toyokawa Kazuhiro Maejima Yuka Yamane Takehiro Suzuki Naoshi Dohmae Masaharu Kogure Daechun Kang David E. Neal Bruce A.J. Ponder Hiroki Yamaue Yusuke Nakamura Ryuji Hamamoto |
| author_facet | Hyun-Soo Cho Shinya Hayami Gouji Toyokawa Kazuhiro Maejima Yuka Yamane Takehiro Suzuki Naoshi Dohmae Masaharu Kogure Daechun Kang David E. Neal Bruce A.J. Ponder Hiroki Yamaue Yusuke Nakamura Ryuji Hamamoto |
| author_sort | Hyun-Soo Cho |
| collection | DOAJ |
| description | It is well known that RB functions are regulated by posttranslational modifications such as phosphorylation and acetylation, but the significance of lysine methylation on RB has not been fully elucidated. Our expression analysis of SMYD2 by quantitative real-time polymerase chain reaction showed that expression levels of SMYD2 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (P < .0001), and its expression levels in tumor tissues were much higher than those of any other normal tissues. SMYD2 knockdown resulted in the suppression of cancer cell growth, and cell cycle analysis indicated that SMYD2 might play a crucial role in the G1/S transition. According to an in vitro methyltransferase assay, we found that SMYD2 methylates RB1 protein, and liquid chromatography-tandem mass spectrometry analysis revealed lysine 810 of RB1 to be methylated by SMYD2. Importantly, this methylation enhanced Ser 807/811 phosphorylation of RB1 both in vitro and in vivo. Furthermore, we demonstrated that methylated RB1 accelerates E2F transcriptional activity and promotes cell cycle progression. SMYD2 is an important oncoprotein in various types of cancer, and SMYD2-dependent RB1 methylation at lysine 810 promotes cell cycle progression of cancer cells. Further study may explore SMYD2-dependent RB1 methylation as a potential therapeutic target in human cancer. |
| first_indexed | 2024-12-21T06:33:55Z |
| format | Article |
| id | doaj.art-6aed5ecb1fce4317af4d8f6f89400bbc |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-21T06:33:55Z |
| publishDate | 2012-06-01 |
| publisher | Elsevier |
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| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-6aed5ecb1fce4317af4d8f6f89400bbc2022-12-21T19:12:56ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-06-0114647648610.1593/neo.12656RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 PhosphorylationHyun-Soo Cho0Shinya Hayami1Gouji Toyokawa2Kazuhiro Maejima3Yuka Yamane4Takehiro Suzuki5Naoshi Dohmae6Masaharu Kogure7Daechun Kang8David E. Neal9Bruce A.J. Ponder10Hiroki Yamaue11Yusuke Nakamura12Ryuji Hamamoto13Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanBiomolecular Characterization Team, RIKEN, Saitama, JapanBiomolecular Characterization Team, RIKEN, Saitama, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanDepartment of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge, Cambridge, UKDepartment of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge, Cambridge, UKSecond Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, JapanIt is well known that RB functions are regulated by posttranslational modifications such as phosphorylation and acetylation, but the significance of lysine methylation on RB has not been fully elucidated. Our expression analysis of SMYD2 by quantitative real-time polymerase chain reaction showed that expression levels of SMYD2 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (P < .0001), and its expression levels in tumor tissues were much higher than those of any other normal tissues. SMYD2 knockdown resulted in the suppression of cancer cell growth, and cell cycle analysis indicated that SMYD2 might play a crucial role in the G1/S transition. According to an in vitro methyltransferase assay, we found that SMYD2 methylates RB1 protein, and liquid chromatography-tandem mass spectrometry analysis revealed lysine 810 of RB1 to be methylated by SMYD2. Importantly, this methylation enhanced Ser 807/811 phosphorylation of RB1 both in vitro and in vivo. Furthermore, we demonstrated that methylated RB1 accelerates E2F transcriptional activity and promotes cell cycle progression. SMYD2 is an important oncoprotein in various types of cancer, and SMYD2-dependent RB1 methylation at lysine 810 promotes cell cycle progression of cancer cells. Further study may explore SMYD2-dependent RB1 methylation as a potential therapeutic target in human cancer.http://www.sciencedirect.com/science/article/pii/S1476558612801035 |
| spellingShingle | Hyun-Soo Cho Shinya Hayami Gouji Toyokawa Kazuhiro Maejima Yuka Yamane Takehiro Suzuki Naoshi Dohmae Masaharu Kogure Daechun Kang David E. Neal Bruce A.J. Ponder Hiroki Yamaue Yusuke Nakamura Ryuji Hamamoto RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation Neoplasia: An International Journal for Oncology Research |
| title | RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation |
| title_full | RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation |
| title_fullStr | RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation |
| title_full_unstemmed | RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation |
| title_short | RB1 Methylation by SMYD2 Enhances Cell Cycle Progression through an Increase of RB1 Phosphorylation |
| title_sort | rb1 methylation by smyd2 enhances cell cycle progression through an increase of rb1 phosphorylation |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612801035 |
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