The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer

Abstract

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

“…Although the synergistic effects of LSD1 inhibitors and other protein inhibitors, such as BRD4 and NAE, have been confirmed, there have not been multitarget drugs based on LSD1 and other proteins. Here, we summarize the combined application of LSD1 inhibitors with other targeted drugs, ,− hoping to provide theoretical guidance for the development of multitarget drugs.…”

“…111 Recently, Metzler et al reported that in PCa, LSD1, and KDM5B exhibited synergistic effects in regulating AR expression and signaling. 97 Following this, they assessed the impact of CPI-455 (a KDM5B inhibitor) alone or in combination with Namoline (an LSD1 inhibitor) on the proliferation and invasion of AR-driven PCa cell lines (Table 2). The results showed that CPI-455 reduced the androgeninduced expression of AR target genes KLK3/PSA and downregulated several genes related to cancer pathways such as Hippo, WNT, and PI3K/AKT.…”

“…Recently, Metzler et al reported that in PCa, LSD1, and KDM5B exhibited synergistic effects in regulating AR expression and signaling . Following this, they assessed the impact of CPI-455 (a KDM5B inhibitor) alone or in combination with Namoline (an LSD1 inhibitor) on the proliferation and invasion of AR-driven PCa cell lines (Table ).…”

Co‐targeting SKP2 and KDM5B inhibits prostate cancer progression by abrogating AKT signaling with induction of senescence and apoptosis

“…Development and progression of CRPC are an intricate process involving the alterations of many molecular pathways, 3 of which a major component is the PI3K/AKT signaling pathway. 4,5 Although there are therapies in clinical trials to treat CRPC (e.g., docetaxel and enzalutamide), resistance to these therapies occurs in most patients, which may lead to malignant progression. Therefore, novel, and effective treatment strategies are needed to improve the therapeutic potential against CRPC.…”

“…Although androgen deprivation therapy (ADT) is the first‐line treatment to primary PCa, relapse is often observed in most PCa patients who ultimately develop castration‐resistant prostate cancer (CRPC). Development and progression of CRPC are an intricate process involving the alterations of many molecular pathways, 3 of which a major component is the PI3K/AKT signaling pathway 4,5 . Although there are therapies in clinical trials to treat CRPC (e.g., docetaxel and enzalutamide), resistance to these therapies occurs in most patients, which may lead to malignant progression.…”