Melatonin decreases androgen-sensitive prostate cancer growth by suppressing SENP1 expression

Lin Hao; Yang Dong; Jun-Jie Zhang; Hou-Guang He; Jian-Gang Chen; Shao-Qi Zhang; Qian-Jin Zhang; Wei Wu; Cong-Hui Han; Zhen-Duo Shi

doi:10.21037/tau-21-1110

Melatonin decreases androgen-sensitive prostate cancer growth by suppressing SENP1 expression

Transl Androl Urol. 2022 Jan;11(1):91-103. doi: 10.21037/tau-21-1110.

Authors

Lin Hao^#^{1

2}, Yang Dong^#^{1

2}, Jun-Jie Zhang^#^{1

2}, Hou-Guang He², Jian-Gang Chen¹, Shao-Qi Zhang¹, Qian-Jin Zhang¹, Wei Wu¹, Cong-Hui Han^#^{1

2}, Zhen-Duo Shi^#²

Affiliations

¹ Medical College of Soochow University, Suzhou, China.
² Department of Urology, Xuzhou central hospital, Xuzhou, China.

^# Contributed equally.

Abstract

Background: Melatonin is a hormone naturally produced by the pineal gland in the brain. In addition to modulating circadian rhythms, it has pleiotropic biological effects including antioxidant, immunomodulatory, and anti-cancer effects. Herein, we report that melatonin has the ability to decrease the growth and metastasis of androgen-dependent prostate cancer.

Methods: To evaluate the anti-cancer effect of melatonin on androgen-sensitive prostate cancer in vitro or in vivo, the effects of cell proliferation, apoptosis, migration and invasion were analyzed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell assay, and immunohistochemistry (IHC), respectively. Next, the interaction between androgen receptor (AR) and SUMO specific protease 1 (SENP1) was detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting, and confirmed by luciferase reporter assay. Furthermore, the Small Ubiquitin-like Modifier (SUMO) proteins are a group of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. (SUMOylation) of histone deacetylases 1 (HDAC1) was measured by proximity ligation assay (PLA).

Results: The treatment of melatonin cripples the transcriptional activity of AR, which is essential for the growth of the androgen-dependent prostate cancer cell, LNCaP. The lower activity of AR was dependent on melatonin induced SUMOylation of HDAC1, which has been established as a key factor for the transcriptional activity of AR. Mechanistically, the effect of melatonin on AR was due to the decreased SENP1 protein level and the subsequent increased HDAC1 SUMOylation level. The overexpression of SENP1 abrogated the anti-cancer ability of melatonin on LNCaP cells.

Conclusions: These findings indicate that melatonin is a suppressor of androgen-dependent prostate cancer tumorigenesis.

Keywords: Melatonin (MT); SUMO specific protease 1 (SENP1); cell growth; prostate cancer.