Abstract
Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.
Highlights
Bladder cancer (BCa) is one of the most common cancers in men, resulting in a reported 8470 new cases and over 17,670 deaths in the United States in 2019 [1]
The epigenetic regulation of androgen receptor (AR) has been extensively studied in prostate cancer, a growing body of evidence has suggested a role for AR in other cancers, including colon, breast, and bladder cancer
We focused on the AR function in bladder cancer, because of its high malignant character, which is known to be related to AR malfunction
Summary
Bladder cancer (BCa) is one of the most common cancers in men, resulting in a reported 8470 new cases and over 17,670 deaths in the United States in 2019 [1]. Recent preclinical studies have suggested that the androgen-mediated AR signaling promotes bladder cancer progression, and blocking this signaling with enzalutamide can strongly impair bladder cancer cell growth [16,17,18]. Another recent study has shed light on the role of the AR in cisplatin-resistant bladder cancer [19]. It is reported that the anti-androgenic drug hydroxyflutamide increased cisplatin sensitivity in cisplatin-resistant bladder cancer cell line T24
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