Cryptotanshinone down‐regulates androgen receptor signaling by modulating lysine‐specific demethylase 1 function

Abstract

Development and progression of prostate cancer are intimately associated with androgen receptor (AR) signaling. The emergence of hormone-refractory prostate cancer and consequent failure of conventional androgen deprivation therapies make it necessary to bypass hormonal resistance by targeting the same signaling pathway at new intervention points. In our study, we showed that cryptotanshinone inhibited the growth of AR-positive prostate cancer cells, suggesting that cryptotanshinone affected AR function. Cryptotanshinone also profoundly inhibited the transcriptional activity of AR and suppressed the expression of several AR-target genes at the mRNA and the protein levels. At the molecular level, cryptotanshinone disrupted the interaction between AR and lysine-specific demethylase 1 (LSD1), and inhibited the complex of AR and LSD1 to the promoter of AR target genes without affecting the protein degradation and translocation of AR. Cryptotanshinone increased the monomethyl and di-methylation of Histone H3 lysine 9 (H3K9), a repressive histone marker which is demethylated and activated by LSD1. These data suggest that cryptotanshinone functions via inhibition of LSD1, a protein that promotes AR-dependent transcriptional activity via derepression of H3K9. In summary, we describe a novel mechanism whereby cryptotanshinone downregulates AR signaling via functional inhibition of LSD1-mediated demethylation of H3K9 and represses the transcriptional activity of AR. Our data suggest that cryptotanshinone can be developed as a potential therapeutic agent for prostate cancer.

Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9® Lead to Promotion versus Suppression of Prostate Cancer Metastasis

“…Because AR co-regulators can determine specific AR targets in different types of cells (43), regulation of AR co-regulator interaction may also change the gene expression profile regarding the metastasis-related genes. A previous study showed that CTS can reverse the demethylation process mediated by LSD1 and inhibit AR transactivation at the epigenetic level (28). It would be interesting to identify the potential regulation of PCa metastasis abilities via epigenetic markers.…”

“…Unlike the currently used anti-androgens that reduce or prevent androgen binding to AR, the newly developed anti-AR compound, ASC-J9, has the unique capability to degrade AR protein in selective cells. On the other hand, CTS also could suppress the AR activity by inhibition of N-terminal and C-terminal interaction or change the histone methylation pattern to reduce the AR transcriptional activity (12,28).…”

Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling

“…Recently, CPT was reported to inhibit the androgen receptor activity and suppress prostate cancer growth in androgen-dependent manner, but the reason for that is not due to the direct bind to androgen receptor and is attributed to its functional inhibition of LSD1-mediated demethylation of H3K9. 19,20 Thanshinone I has been reported to induce apoptosis of breast cancer cells, 27 so it is possible that Thanshinone I also could inhibit ER transcriptional activity due to the similarity of the chemical structures of Thanshinone I and CPT. However, we found that anshinones I less effectively inhibited E2-induced transcriptional activity and expression of the ER target gene (pS2, and Cat D) in the presence of E2, compared with CPT, which is consistent with the same inhibitory effect of anshinones I on ERpositive as well as ER-negative cancer cells.…”

“…[14][15][16][17] Recently, CPT has also been reported to have obvious antitumor activity in a variety of cancer cells, including prostate carcinoma, hepatocarcinoma, rhabdomyosarcoma and melanoma cells. [18][19][20][21][22][23] In breast carcinoma cells, CPT has been shown to inhibit MCF7 cell proliferation by suppressing mTOR mediated CyclinD1 expression and Rb phosphorylation that lead to MCF7 cell apoptosis by inducing stress in the endoplasmic reticulum (ER). 24,25 However, it is not known whether CPT has any effects on estrogen-stimulated ER signaling and estrogen /ER mediated cancer cell growth.…”

LSD1-mediated epigenetic modification contributes to ovarian cancer cell migration and invasion

“…LSD1 is frequently overexpressed in lung cancer (5,6), breast cancer (7), prostate cancer (8,9), and liver cancer (10). Importantly, overexpression of LSD1 promotes the growth and invasion of various types of cancer cells, and contributes to human carcinogenesis by regulating the expression of genes involved in various chromatin-modifying pathways (6).…”