ABSTRACT Prostate cancer (PCa) is the most frequently diagnosed cancer among men. However, the major modifiable risk factors for PCa are poorly known and its specific mechanism of progression remains unclear. Here we reported that, in prostate cancer cells, the autophagy level was elevated under hypoxic condition, as well as the mRNA and protein level of ATG5, which is an important gene related to autophagy. Furthermore, we found HIF1α could directly bind to the promoter of ATG5 and promote the expression of ATG5 on transcriptional level by luciferase assay and ChIP assay. Intriguingly, overexpression of HIF1α by HIF1α-M could increase tumor size and the effect could be abolished by knockdown ATG5 by si-ATG5 in BALB/cA-nu/nu nude mice. Importantly, HIF1α could also promote the metastasis of PC-3 cells by upregulating the ATG5 and autophagy level and knockdown ATG5 and inhibition autophagy both could abolish the effect of overexpression of HIF1α on the migration of PC-3 cells. Taken together, our results, for the first time, proved that HIF1α could promote the proliferation and migration of PC-3 cells by direct upregulating ATG5 and autophagy level in PC-3 prostate cancer cells. Our findings not only provide new perspective for the relationship between hypoxia and autophagy, but also add new potential therapeutic regimens for the treatment of prostate cancers.

中文翻译：

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HIF1α通过增加ATG5表达促进前列腺癌进展

摘要 前列腺癌 (PCa) 是男性中最常被诊断出的癌症。然而，PCa 的主要可改变危险因素知之甚少，其进展的具体机制仍不清楚。在这里我们报道，在前列腺癌细胞中，在缺氧条件下自噬水平升高，以及与自噬相关的重要基因 ATG5 的 mRNA 和蛋白质水平。此外，我们通过荧光素酶测定和 ChIP 测定发现 HIF1α 可以直接与 ATG5 的启动子结合并在转录水平上促进 ATG5 的表达。有趣的是，在 BALB/cA-nu/nu 裸鼠中，HIF1α-M 过表达 HIF1α 可以增加肿瘤大小，并且可以通过 si-ATG5 敲低 ATG5 来消除这种作用。重要的，HIF1α还可以通过上调ATG5和自噬水平促进PC-3细胞的转移，敲低ATG5和抑制自噬都可以消除HIF1α过表达对PC-3细胞迁移的影响。总之，我们的结果首次证明HIF1α可以通过直接上调PC-3前列腺癌细胞中的ATG5和自噬水平来促进PC-3细胞的增殖和迁移。我们的发现不仅为缺氧与自噬之间的关系提供了新的视角，而且为前列腺癌的治疗增加了新的潜在治疗方案。证明HIF1α可以通过直接上调PC-3前列腺癌细胞中的ATG5和自噬水平来促进PC-3细胞的增殖和迁移。我们的发现不仅为缺氧与自噬之间的关系提供了新的视角，而且为前列腺癌的治疗增加了新的潜在治疗方案。证明HIF1α可以通过直接上调PC-3前列腺癌细胞中的ATG5和自噬水平来促进PC-3细胞的增殖和迁移。我们的发现不仅为缺氧与自噬之间的关系提供了新的视角，而且为前列腺癌的治疗增加了新的潜在治疗方案。