Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation
The circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: <i>PbsnCre+</i>; <i>Bmal1<sup>fx/fx</sup></i>) and immortalized human prostat...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/19/11272 |
| _version_ | 1797479143230668800 |
|---|---|
| author | Masakatsu Ueda Jin Kono Atsushi Sengiku Yoshiyuki Nagumo Bryan J. Mathis Shigeki Shimba Makoto Mark Taketo Takashi Kobayashi Osamu Ogawa Hiromitsu Negoro |
| author_facet | Masakatsu Ueda Jin Kono Atsushi Sengiku Yoshiyuki Nagumo Bryan J. Mathis Shigeki Shimba Makoto Mark Taketo Takashi Kobayashi Osamu Ogawa Hiromitsu Negoro |
| author_sort | Masakatsu Ueda |
| collection | DOAJ |
| description | The circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: <i>PbsnCre+</i>; <i>Bmal1<sup>fx/fx</sup></i>) and immortalized human prostate cells (RWPE-1 and WPMY-1) to elucidate the role of the peripheral prostate clock on prostate growth. Bmal1 KO resulted in significantly decreased ventral and dorsolateral lobes with less Ki-67-positive epithelial cells than the controls. Next, the cap analysis of gene expression revealed that genes associated with cell cycles were differentially expressed in the pBmal1 KO prostate. <i>Cdkn1a</i> (coding p21) was diurnally expressed in the control mouse prostate, a rhythm which was disturbed in pBmal1 KO. Meanwhile, the knockdown of BMAL1 in epithelial RWPE-1 and stromal WPMY-1 cell lines decreased proliferation. Furthermore, RWPE-1 BMAL1 knockdown increased G0/G1-phase cell numbers but reduced S-phase numbers. These findings indicate that core clock gene Bmal1 is involved in prostate growth via the modulation of the cell cycle and provide a rationale for further research to link the pathogenesis of benign prostatic hyperplasia or cancer with the circadian clock. |
| first_indexed | 2024-03-09T21:41:22Z |
| format | Article |
| id | doaj.art-d75f62db27b143299122aa74ed018f37 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:41:22Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d75f62db27b143299122aa74ed018f372023-11-23T20:30:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123191127210.3390/ijms231911272Bmal1 Regulates Prostate Growth via Cell-Cycle ModulationMasakatsu Ueda0Jin Kono1Atsushi Sengiku2Yoshiyuki Nagumo3Bryan J. Mathis4Shigeki Shimba5Makoto Mark Taketo6Takashi Kobayashi7Osamu Ogawa8Hiromitsu Negoro9Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, JapanDepartment of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, JapanDepartment of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, JapanDepartment of Urology, Faculty of Medicine, University of Tsukuba, Tskuba 305-8575, JapanInternational Medical Center, University of Tsukuba Affiliated Hospital, Tsukuba 305-8576, JapanDepartment of Health Science, School of Pharmacy, Nihon University, Chiba 245-8555, JapaniACT-Colon Cancer Project, Kyoto University Hospital, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, JapanDepartment of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, JapanDepartment of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, JapanDepartment of Urology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, JapanThe circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: <i>PbsnCre+</i>; <i>Bmal1<sup>fx/fx</sup></i>) and immortalized human prostate cells (RWPE-1 and WPMY-1) to elucidate the role of the peripheral prostate clock on prostate growth. Bmal1 KO resulted in significantly decreased ventral and dorsolateral lobes with less Ki-67-positive epithelial cells than the controls. Next, the cap analysis of gene expression revealed that genes associated with cell cycles were differentially expressed in the pBmal1 KO prostate. <i>Cdkn1a</i> (coding p21) was diurnally expressed in the control mouse prostate, a rhythm which was disturbed in pBmal1 KO. Meanwhile, the knockdown of BMAL1 in epithelial RWPE-1 and stromal WPMY-1 cell lines decreased proliferation. Furthermore, RWPE-1 BMAL1 knockdown increased G0/G1-phase cell numbers but reduced S-phase numbers. These findings indicate that core clock gene Bmal1 is involved in prostate growth via the modulation of the cell cycle and provide a rationale for further research to link the pathogenesis of benign prostatic hyperplasia or cancer with the circadian clock.https://www.mdpi.com/1422-0067/23/19/11272circadianclock<i>Cdkn1a</i>p21development |
| spellingShingle | Masakatsu Ueda Jin Kono Atsushi Sengiku Yoshiyuki Nagumo Bryan J. Mathis Shigeki Shimba Makoto Mark Taketo Takashi Kobayashi Osamu Ogawa Hiromitsu Negoro Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation International Journal of Molecular Sciences circadian clock <i>Cdkn1a</i> p21 development |
| title | Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation |
| title_full | Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation |
| title_fullStr | Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation |
| title_full_unstemmed | Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation |
| title_short | Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation |
| title_sort | bmal1 regulates prostate growth via cell cycle modulation |
| topic | circadian clock <i>Cdkn1a</i> p21 development |
| url | https://www.mdpi.com/1422-0067/23/19/11272 |
| work_keys_str_mv | AT masakatsuueda bmal1regulatesprostategrowthviacellcyclemodulation AT jinkono bmal1regulatesprostategrowthviacellcyclemodulation AT atsushisengiku bmal1regulatesprostategrowthviacellcyclemodulation AT yoshiyukinagumo bmal1regulatesprostategrowthviacellcyclemodulation AT bryanjmathis bmal1regulatesprostategrowthviacellcyclemodulation AT shigekishimba bmal1regulatesprostategrowthviacellcyclemodulation AT makotomarktaketo bmal1regulatesprostategrowthviacellcyclemodulation AT takashikobayashi bmal1regulatesprostategrowthviacellcyclemodulation AT osamuogawa bmal1regulatesprostategrowthviacellcyclemodulation AT hiromitsunegoro bmal1regulatesprostategrowthviacellcyclemodulation |