Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
Nucleic Acids Res. 2024 Jun 10;52(10):5610-5623. doi: 10.1093/nar/gkae206.
The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting in resistance to AR-targeted therapies. In this study, we examined the chromatin landscape of AR-positive prostate cancer cells post-exposure to the AR inhibitor enzalutamide. We identified a novel regulator of cell plasticity, the homeobox transcription factor SIX2, whose motif is enriched in accessible chromatin regions after treatment. Depletion of SIX2 in androgen-independent PC-3 prostate cancer cells induced a switch from a stem-like to an epithelial state, resulting in reduced cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects were mediated through the downregulation of the Wnt/β-catenin signalling pathway and subsequent reduction of nuclear β-catenin. Collectively, our findings provide compelling evidence that the depletion of SIX2 may represent a promising strategy for overcoming the cell plasticity mechanisms driving antiandrogen resistance in prostate cancer.
雄激素受体（AR）抑制剂在前列腺癌中的应用会导致细胞谱系可塑性增加，从而产生对 AR 靶向治疗的耐药性。在这项研究中，我们研究了 AR 阳性前列腺癌细胞在暴露于 AR 抑制剂恩扎卢胺后的染色质景观。我们鉴定了一种新型细胞可塑性调节因子同源盒转录因子 SIX2，其基序在治疗后富含可及染色质区域。在雄激素非依赖性 PC-3 前列腺癌细胞中敲低 SIX2 会诱导从干细胞样状态到上皮样状态的转变，从而降低体外和体内的癌症相关特性，如增殖、集落形成和转移。这些效应是通过下调 Wnt/β-catenin 信号通路和随后减少核β-catenin 来介导的。总之，我们的研究结果提供了有力的证据，表明敲低 SIX2 可能代表一种有前途的策略，可以克服导致前列腺癌抗雄激素耐药性的细胞可塑性机制。
