Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
Ecotoxicol Environ Saf. 2022 Aug;241:113724. doi: 10.1016/j.ecoenv.2022.113724. Epub 2022 Jun 2.
Hexavalent chromium [Cr(VI)], one common environmental contaminant, has long been recognized as a carcinogen associated with several malignancies, such as lung cancer, but little information was available about the effects of its low-dose environmental exposure in prostate cancer. Our previous study has shown that low-dose Cr(VI) exposure could promote prostate cancer(PCa) cell growth in vitro and in vivo. In the present study, we furthermore found that low-dose Cr(VI) exposure could induce DNA demethylation in PCa cells. Based on our transcriptome sequencing data and DNA methylation database, we further identified MAGEB2 as a potential effector target that contributed to tumor-promoting effect of low-dose Cr(VI) exposure in PCa. In addition, we demonstrated that MAGEB2 was upregulated in PCa and its knockdown restrained PCa cell proliferation and tumor growth in vitro and in vivo. Moreover, Co-IP and point mutation experiments confirmed that MAGEB2 could bind to the NH-terminal NTD domain of AR through the F-box in the MAGE homology domain, and then activated AR through up-regulating its downstream targets PSA and NX3.1. Together, low-dose Cr(VI) exposure can induce DNA demethylation in prostate cancer cells, and promote cell proliferation via activating MAGEB2-AR signaling pathway. Thus, inhibition of MAGEB2-AR signaling is a novel and promising strategy to reverse low-dose Cr(VI) exposure-induced prostate tumor progression, also as effective adjuvant therapy for AR signaling-dependent PCa.
六价铬[Cr(VI)]是一种常见的环境污染物，长期以来一直被认为是与多种恶性肿瘤相关的致癌物，如肺癌，但关于其环境低剂量暴露对前列腺癌的影响知之甚少。我们之前的研究表明，低剂量 Cr(VI)暴露可以促进前列腺癌细胞的体外和体内生长。在本研究中，我们进一步发现低剂量 Cr(VI)暴露可以诱导前列腺癌细胞中的 DNA 去甲基化。基于我们的转录组测序数据和 DNA 甲基化数据库，我们进一步确定 MAGEB2 是一个潜在的效应靶标，它有助于低剂量 Cr(VI)暴露在前列腺癌中的促肿瘤作用。此外，我们证明 MAGEB2 在前列腺癌中上调，其敲低抑制了前列腺癌细胞的体外和体内增殖和肿瘤生长。此外，Co-IP 和点突变实验证实，MAGEB2 可以通过 MAGE 同源结构域中的 F 盒与 AR 的 NH-末端 NTD 结构域结合，然后通过上调其下游靶标 PSA 和 NX3.1 来激活 AR。总之，低剂量 Cr(VI)暴露可以诱导前列腺癌细胞中的 DNA 去甲基化，并通过激活 MAGEB2-AR 信号通路促进细胞增殖。因此，抑制 MAGEB2-AR 信号通路是一种新颖而有前途的策略，可以逆转低剂量 Cr(VI)暴露诱导的前列腺肿瘤进展，也可作为 AR 信号依赖性前列腺癌的有效辅助治疗。
