Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells

Abstract

Background The aldo-keto reductase 1C3 (AKR1C3) has been heavily implicated in the propagation of prostate malignancy. AKR1C3 protein is elevated within prostate cancer tissue, it contributes to the formation of androgens and downstream stimulation of the androgen receptor (AR). Elevated expression of AKR1C3 is also reported in acute myeloid leukemia but the target nuclear receptors have been identified as members of the peroxisome-proliferator activated receptor (PPARs) subfamily. Thus, AKR1C3 cancer biology is likely to be tissue dependent and hormonally linked to the availability of ligands for both the steroidogenic and non-steroidogenic nuclear receptors. Methods In the current study we investigated the potential for AKR1C3 to regulate the availability of prostaglandin-derived ligands for PPARg mainly, prostaglandin J2 (PGJ2). Using prostate cancer cell lines with stably reduced AKR1C3 levels we examined the impact of AKR1C3 upon proliferation mediated by PPAR ligands. Results These studies revealed knockdown of AKR1C3 had no effect upon the sensitivity of androgen receptor independent prostate cancer cells towards PPAR ligands. However, the reduction of levels of AKR1C3 was accompanied by a significantly reduced mRNA expression of a range of HDACs, transcriptional co-regulators, and increased sensitivity towards SAHA, a clinically approved histone deacetylase inhibitor. Conclusions These results suggest a hitherto unidentified link between AKR1C3 levels and the epigenetic status in prostate cancer cells. This raises an interesting possibility of a novel rational to target AKR1C3, the utilization of AKRIC3 selective inhibitors in combination with HDAC inhibition as part of novel epigenetic therapies in androgen deprivation therapy recurrent prostate cancer.

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

“…Knockdown of AKR1C3 was accompanied by a significantly reduced expression of a range of histone deacetylases, transcriptional co-regulators, and increased sensitivity towards SAHA, a clinically approved histone deacetylase inhibitor. [85] Looking beyond PCa, UGT2B17 has been identified as a disease accelerator in chronic lymphocytic leukemia [86], and knockdown of UGT2B17 in an endometrial carcinoma cell line resulted in an increase in apoptosis in association with downregulation of the anti-apoptotic protein Mcl-1, and upregulation of the pro-apoptotic target of Mcl-1, Puma [87]. While the mechanism of UGT2B17 involvement in these tumors remains to be elucidated, these reports underscore the potential role of these enzymes in non-steroid metabolizing capacities.…”

AKR1C3 silencing inhibits autophagy‐dependent glycolysis in thyroid cancer cells by inactivating ERK signaling

“…As reported, AKR1C3 is a multifunctional enzyme that catalyzes multiple hormones and xenobiotic metabolism (Dufort et al, 1996; Matsuura et al, 1998). A growing number of studies have shown that overexpressed AKR1C3 occurs in multiple types of human cancer and is involved in the development of human cancer and chemotherapy resistance, such as hepatocellular carcinoma, prostate cancer, breast cancer and esophageal cancer (Doig et al, 2016; Li, 2018a; Pan et al, 2022; Xu et al, 2017). More intriguingly, AKR1C3 exhibits elevated expression in thyroid cancer tissues, and high AKR1C3 expression tends to have a poor prognosis (Wang et al, 2022).…”

Effects and mechanisms of AMIGO2 in proliferation, migration and drug resistance of bladder cancer

“…Interestingly, as previous studies stated, AKR1C1 could mediate the invasive potential and drug resistance of metastatic bladder cancer cells, and AKR1C1 was highly expressed in metastatic lesions of human bladder cancer patients 29 . AKR1C3, comes from the same family as AKR1C1, has not been proved to have similar functions as AKR1C1 in bladder cancer, but it is often overexpressed in prostate cancer tissues and prostate cancer cell lines 30 . AKR1C3 catalyzes the formation of prostaglandin (PG) F2α and 11β-PGF2α from PGH2 and PGD2, respectively 31 .…”