{"title":"KLHL5通过促进细胞周期进程和抑制凋亡细胞死亡参与结直肠癌细胞存活。","authors":"Kyosuke Habu, Yosuke Matsuoka, Hiromi Hiyoshi, Jun Nakayama, Katsuya Watanabe, Sota Tate, Tomohisa Sakaue, Junko Murai, Konomu Uno, Hirotada Nishie, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Yuji Watanabe, Taro Oshikiri, Shigeki Higashiyama","doi":"10.1111/cas.70108","DOIUrl":null,"url":null,"abstract":"<p><p>Kelch-like protein 5 (KLHL5) is highly expressed in colorectal cancer (CRC) compared to that in adjacent normal mucosa, and its expression level increases with CRC stage, showing a correlation with poor prognostic factors. However, its functional role in the malignant progression still remains unknown. To elucidate the role of KLHL5 in CRC, we characterized human CRC cell lines, including HCT116 and SW480, under KLHL5-depleted conditions. KLHL5-depleted HCT116 and SW480 cells suppressed their growth and migration in culture. Further duration induced cell death characterized by apoptotic cell death with down-regulation of antiapoptotic factor Bcl-2 and up-regulation of proapoptotic factors Bac, Boc, Puma, Bid, Noxa, and Bik. Proteomic analyses indicated KLHL5 depletion suppressed cell cycle progression by affecting multiple pathways, including the activation of the G2/M DNA damage pathway and inhibition of the G1/S transition. Further biochemical and cell biological analyses revealed the downregulation of CDT1 and CDC6 proteins, which are essential factors for the initiation of DNA replication, and the downregulation of cyclins A and B, which are essential factors for the progression of S and G2/M phases. Arrested cells undergo apoptotic cell death. Taken together, these data strongly indicate that KLHL5 expression in CRC serves as a survival factor to strengthen the cell cycle and protect against apoptotic cell death under harsh tumor microenvironments.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"KLHL5 Contributes to Colorectal Cancer Cell Survival by Promoting Cell Cycle Progression and Suppressing Apoptotic Cell Death.\",\"authors\":\"Kyosuke Habu, Yosuke Matsuoka, Hiromi Hiyoshi, Jun Nakayama, Katsuya Watanabe, Sota Tate, Tomohisa Sakaue, Junko Murai, Konomu Uno, Hirotada Nishie, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Yuji Watanabe, Taro Oshikiri, Shigeki Higashiyama\",\"doi\":\"10.1111/cas.70108\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Kelch-like protein 5 (KLHL5) is highly expressed in colorectal cancer (CRC) compared to that in adjacent normal mucosa, and its expression level increases with CRC stage, showing a correlation with poor prognostic factors. However, its functional role in the malignant progression still remains unknown. To elucidate the role of KLHL5 in CRC, we characterized human CRC cell lines, including HCT116 and SW480, under KLHL5-depleted conditions. KLHL5-depleted HCT116 and SW480 cells suppressed their growth and migration in culture. Further duration induced cell death characterized by apoptotic cell death with down-regulation of antiapoptotic factor Bcl-2 and up-regulation of proapoptotic factors Bac, Boc, Puma, Bid, Noxa, and Bik. Proteomic analyses indicated KLHL5 depletion suppressed cell cycle progression by affecting multiple pathways, including the activation of the G2/M DNA damage pathway and inhibition of the G1/S transition. Further biochemical and cell biological analyses revealed the downregulation of CDT1 and CDC6 proteins, which are essential factors for the initiation of DNA replication, and the downregulation of cyclins A and B, which are essential factors for the progression of S and G2/M phases. Arrested cells undergo apoptotic cell death. Taken together, these data strongly indicate that KLHL5 expression in CRC serves as a survival factor to strengthen the cell cycle and protect against apoptotic cell death under harsh tumor microenvironments.</p>\",\"PeriodicalId\":48943,\"journal\":{\"name\":\"Cancer Science\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cas.70108\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cas.70108","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
KLHL5 Contributes to Colorectal Cancer Cell Survival by Promoting Cell Cycle Progression and Suppressing Apoptotic Cell Death.
Kelch-like protein 5 (KLHL5) is highly expressed in colorectal cancer (CRC) compared to that in adjacent normal mucosa, and its expression level increases with CRC stage, showing a correlation with poor prognostic factors. However, its functional role in the malignant progression still remains unknown. To elucidate the role of KLHL5 in CRC, we characterized human CRC cell lines, including HCT116 and SW480, under KLHL5-depleted conditions. KLHL5-depleted HCT116 and SW480 cells suppressed their growth and migration in culture. Further duration induced cell death characterized by apoptotic cell death with down-regulation of antiapoptotic factor Bcl-2 and up-regulation of proapoptotic factors Bac, Boc, Puma, Bid, Noxa, and Bik. Proteomic analyses indicated KLHL5 depletion suppressed cell cycle progression by affecting multiple pathways, including the activation of the G2/M DNA damage pathway and inhibition of the G1/S transition. Further biochemical and cell biological analyses revealed the downregulation of CDT1 and CDC6 proteins, which are essential factors for the initiation of DNA replication, and the downregulation of cyclins A and B, which are essential factors for the progression of S and G2/M phases. Arrested cells undergo apoptotic cell death. Taken together, these data strongly indicate that KLHL5 expression in CRC serves as a survival factor to strengthen the cell cycle and protect against apoptotic cell death under harsh tumor microenvironments.
期刊介绍:
Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports.
Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.