Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA.
Nat Commun. 2021 Nov 4;12(1):6377. doi: 10.1038/s41467-021-26612-1.
Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.
用于治疗前列腺癌的内分泌疗法会抑制雄激素受体 (AR) 转录因子。在大多数情况下，AR 活性会在治疗过程中恢复，并导致去势抵抗性前列腺癌 (CRPC) 的进展。然而，治疗也可以促进谱系可塑性，并选择 AR 不依赖的表型，这些表型通常是致命的。在这里，我们证明干细胞转录因子 Krüppel-like factor 5 (KLF5) 在接受内分泌治疗之前在前列腺癌中含量较低或不存在，但在包括显示谱系可塑性的 CRPC 中的一部分中被诱导。KLF5 和 AR 在染色质上物理相互作用，并驱动相反的转录程序，其中 KLF5 促进细胞迁移、非锚定生长和基底上皮细胞表型。我们确定 ERBB2 是一个转录融合点，显示出 KLF5 的激活和 AR 的抑制。ERBB2 抑制剂优先阻断 KLF5 驱动的致癌表型。这些发现表明 KLF5 是一种癌基因，它可以在 CRPC 中上调，以对抗 AR 活性并促进谱系可塑性。
