Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway
A number of histone methyltransferases have been identified and biochemically characterized, but the pathologic roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays important roles in human carc...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2011-10-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558611800771 |
| _version_ | 1818918811607236608 |
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| author | Gouji Toyokawa Hyun-Soo Cho Ken Masuda Yuka Yamane Masanori Yoshimatsu Shinya Hayami Masashi Takawa Yukiko Iwai Yataro Daigo Eiju Tsuchiya Tatsuhiko Tsunoda Helen I. Field John D. Kelly David E. Neal Yoshihiko Maehara Bruce A.J. Ponder Yusuke Nakamura Ryuji Hamamoto |
| author_facet | Gouji Toyokawa Hyun-Soo Cho Ken Masuda Yuka Yamane Masanori Yoshimatsu Shinya Hayami Masashi Takawa Yukiko Iwai Yataro Daigo Eiju Tsuchiya Tatsuhiko Tsunoda Helen I. Field John D. Kelly David E. Neal Yoshihiko Maehara Bruce A.J. Ponder Yusuke Nakamura Ryuji Hamamoto |
| author_sort | Gouji Toyokawa |
| collection | DOAJ |
| description | A number of histone methyltransferases have been identified and biochemically characterized, but the pathologic roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays important roles in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNA targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Cell cycle analysis by flow cytometry indicated that knockdown of WHSC1 decreased the cell population of cancer cells at the S phase while increasing that at the G2/M phase. WHSC1 interacts with some proteins related to the WNT pathway including β-catenin and transcriptionally regulates CCND1, the target gene of the β-catenin/Tcf-4 complex, through histone H3 at lysine 36 trimethylation. This is a novel mechanism for WNT pathway dysregulation in human carcinogenesis, mediated by the epigenetic regulation of histone H3. Because expression levels of WHSC1 are significantly low in most normal tissue types, it should be feasible to develop specific and selective inhibitors targeting the enzyme as antitumor agents that have a minimal risk of adverse reaction. |
| first_indexed | 2024-12-20T00:55:54Z |
| format | Article |
| id | doaj.art-c70b2d1d1a97462b8518a9abccb09930 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-20T00:55:54Z |
| publishDate | 2011-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-c70b2d1d1a97462b8518a9abccb099302022-12-21T19:59:06ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022011-10-01131088789810.1593/neo.11048Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt PathwayGouji Toyokawa0Hyun-Soo Cho1Ken Masuda2Yuka Yamane3Masanori Yoshimatsu4Shinya Hayami5Masashi Takawa6Yukiko Iwai7Yataro Daigo8Eiju Tsuchiya9Tatsuhiko Tsunoda10Helen I. Field11John D. Kelly12David E. Neal13Yoshihiko Maehara14Bruce A.J. Ponder15Yusuke Nakamura16Ryuji Hamamoto17Laboratory 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, 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, JapanDepartment of Pathology, Saitama Cancer Center, Saitama, JapanLaboratory for Medical Informatics, RIKEN, Kanagawa, JapanDepartment of Genetics, University of Cambridge, Cambridge, UKDepartment of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge, Cambridge, UKDivision of Surgery & Interventional Science, UCL Medical School, University College London, London, UKDepartment of Surgery and Science, Graduate School of Medical Science, Kyusyu University, Fukuoka, JapanDepartment of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge, Cambridge, UKLaboratory 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, JapanA number of histone methyltransferases have been identified and biochemically characterized, but the pathologic roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays important roles in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNA targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Cell cycle analysis by flow cytometry indicated that knockdown of WHSC1 decreased the cell population of cancer cells at the S phase while increasing that at the G2/M phase. WHSC1 interacts with some proteins related to the WNT pathway including β-catenin and transcriptionally regulates CCND1, the target gene of the β-catenin/Tcf-4 complex, through histone H3 at lysine 36 trimethylation. This is a novel mechanism for WNT pathway dysregulation in human carcinogenesis, mediated by the epigenetic regulation of histone H3. Because expression levels of WHSC1 are significantly low in most normal tissue types, it should be feasible to develop specific and selective inhibitors targeting the enzyme as antitumor agents that have a minimal risk of adverse reaction.http://www.sciencedirect.com/science/article/pii/S1476558611800771 |
| spellingShingle | Gouji Toyokawa Hyun-Soo Cho Ken Masuda Yuka Yamane Masanori Yoshimatsu Shinya Hayami Masashi Takawa Yukiko Iwai Yataro Daigo Eiju Tsuchiya Tatsuhiko Tsunoda Helen I. Field John D. Kelly David E. Neal Yoshihiko Maehara Bruce A.J. Ponder Yusuke Nakamura Ryuji Hamamoto Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway Neoplasia: An International Journal for Oncology Research |
| title | Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway |
| title_full | Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway |
| title_fullStr | Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway |
| title_full_unstemmed | Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway |
| title_short | Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway |
| title_sort | histone lysine methyltransferase wolf hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the wnt pathway |
| url | http://www.sciencedirect.com/science/article/pii/S1476558611800771 |
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