Histone Demethylase LSD1 Regulates Kidney Cancer Progression by Modulating Androgen Receptor Activity.

Kyoung-Hwa Lee,Byung-Chan Kim,Seung-Hwan Jeong,Ja Hyeon Ku,Hyeon Hoe Kim,Chang Wook Jeong,Cheol Kwak

doi:10.3390/ijms21176089

Abstract

Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially important for finding new drugs. We focused on androgen receptor (AR) regulation by its epigenetic co-regulator lysine-specific histone demethylase 1 (LSD1) in kidney cancer development. LSD1 knock-down in kidney cancer cells decreased expression of AR target genes. Moreover, the binding of AR to target gene promoters was reduced and histone methylation status was changed in LSD1 knock-down kidney cancer cells. LSD1 knock-down also slowed growth and decreased the migration ability of kidney cancer cells. We found that pargyline, known as a LSD1 inhibitor, can reduce AR activity in kidney cancer cells. The treatment of kidney cancer cells with pargyline delayed growth and repressed epithelial–mesenchymal transition (EMT) markers. These effects were additively enhanced by co-treatment with the AR inhibitor enzalutamide. Down-regulation of LSD1 in renal cancer cells (RCC) attenuated in vivo tumor growth in a xenograft mouse model. These results provide evidence that LSD1 can regulate kidney cancer cell growth via epigenetic control of AR transcription factors and that LSD1 inhibitors may be good candidate drugs for treating kidney cancer.

Highlights

Kidney cancer is one of the most lethal types of cancer, accounting for ~3% of malignancies in the USA in 2018 [1]
We assessed whether lysine-specific histone demethylase 1 (LSD1) modulation affects androgen receptor (AR) activity in kidney cancer cells
We found that LSD1 binds to AR target genes including KLK2, KLK3, and transmembrane protease serine subtype 2 (TMPRSS2) in kidney cancer cells, and confirmed that the binding decreased in LSD1 short hairpin RNA (shRNA)-expressing cells (Figure 1D)

Summary

Introduction

Kidney cancer is one of the most lethal types of cancer, accounting for ~3% of malignancies in the USA in 2018 [1]. In contrast with its function in other cancers, the expression of AR in RCC is negatively correlated with cancer development and survival rate [10,11]; some reports show that the AR level influences the initiation and metastatic route of RCC [12,13,14]. These conflicting results might suggest that a change in AR activity, rather than expression level, is more important in kidney cancer. To analyse AR function in kidney cancer, we selected Caki-2 cells among several RCC cell lines because there are reports of AR expression in this cell line [15]

Methods

Results

Conclusion