Abstract
Prostate cancer (PCa) is the most common cancer in men and the fifth leading cause of cancer death worldwide. Unfortunately, castration-resistant prostate cancer (CRPCa) is incurable with surgical treat and prone to drug resistance. Therefore, it is of great importance to find a new target for treatment. LSD1 is up-regulated in PCa and related with prognosis. The high-expression LSD1 has been shown to be a potential target for treatment and is widely studied for its demethylase-activity. However, its demethylation-independent function remains to be elusive in PCa. Recent study shows that LSD1 can destabilize cancer suppressor protein FBXW7 without demethylation-function. Hence, we hope to investigate the impact of non-canonical function of LSD1 on PCa cell survival. We over-expressed FBXW7 gene through plasmid vector in LNCaP and PC3 cell lines and the result shows that up-regulated FBXW7 can suppress the viability of PC cell through suppressing oncoproteins, such as c-MYC, NOTCH-1. After FBXW7 function experiment on PC cell, we knock-down LSD1 gene in the same kinds of cell lines. In western blot assay, we detected that down-regulation of LSD1 will cause the increasing of FBXW7 protein level and decreasing of its targeting oncoproteins. And mRNA level of FBXW7 did not change significantly after LSD1 knock-down, which means LSD1 may destabilize FBXW7 by protein-protein interactions. Moreover, exogenous wild type LSD1 and catalytically deficient mutant K661A both can abrogate previous effect of LSD1 knock-down. Consequently, LSD1 may promote PC cell survival by destabilizing FBXW7 without its demethylase-activity. Next, we compared two kinds inhibitors, and found that SP-2509 (Allosteric inhibitor) treatment suppress the cancer cell survival by blocking the LSD1–FBXW7 interaction, which is an effect that GSK-2879552 (catalytic inhibitor) cannot achieve. This work revealed a pivotal function of LSD1 in PCa, and indicated a new direction of LSD1 inhibitor research for PCa treatment.
Highlights
As of 2018, global cancer statistics show that prostate cancer has become the second most common cancer in men and the fifth leading cause of cancer death [1]
LSD1 is highly expressed in various type of prostate cancer [10, 11] while the expression of FBXW7 decreased in prostate cancer [12]
Immunohistochemical staining showed that LSD1 and FBXW7 proteins are both mainly localized in nuclei of luminal cells of prostate carcinoma cells
Summary
As of 2018, global cancer statistics show that prostate cancer has become the second most common cancer in men and the fifth leading cause of cancer death [1]. In this disease, advanced prostate cancer is incurable and has become the second leading cause of cancer-related death in the United States [1]. Radical prostatectomy is always the first choice. Androgen-deprivation therapy (ADT) is the standard treatment for patients with advanced prostate cancer. There is an urgent need to find new targets and treatment methods for the treatment of advanced prostate cancer [2, 3]
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