Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Nat Commun. 2020 Feb 21;11(1):997. doi: 10.1038/s41467-020-14737-8.
Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation. It remains elusive whether post-translational modifications of transcription factors can differentially determine adult stem/progenitor cell fate. Here we report that, in human and mouse prostates, Klf5 is expressed in both basal and luminal cells, with basal cells preferentially expressing acetylated Klf5. Functionally, Klf5 is indispensable for maintaining basal progenitors, their luminal differentiation, and the proliferation of their basal and luminal progenies. Acetylated Klf5 is also essential for basal progenitors' maintenance and proper luminal differentiation, as deacetylation of Klf5 causes excess basal-to-luminal differentiation; attenuates androgen-mediated organoid organization; and retards postnatal prostate development. In basal progenitor-derived luminal cells, Klf5 deacetylation increases their proliferation and attenuates their survival and regeneration following castration and subsequent androgen restoration. Mechanistically, Klf5 deacetylation activates Notch signaling. Klf5 and its acetylation thus contribute to postnatal prostate development and regeneration by controlling basal progenitor cell fate.
前列腺的发育依赖于细胞增殖和分化的平衡，已知乙酰化的 KLF5 可改变上皮细胞的增殖。然而，转录因子的翻译后修饰是否能差异决定成体干细胞/祖细胞的命运仍不清楚。在这里，我们报告在人和小鼠前列腺中，Klf5 在基底细胞和腔细胞中均有表达，而基底细胞优先表达乙酰化的 Klf5。功能上，Klf5 对于维持基底祖细胞、它们的腔分化以及它们的基底和腔祖细胞的增殖是必不可少的。乙酰化的 Klf5 对于维持基底祖细胞和适当的腔分化也是必不可少的，因为 Klf5 的去乙酰化会导致基底到腔的过度分化；减弱雄激素介导的类器官组织；并延缓产后前列腺的发育。在基底祖细胞衍生的腔细胞中，Klf5 的去乙酰化会增加其增殖，并在去势和随后的雄激素恢复后减弱其存活和再生。从机制上讲，Klf5 的去乙酰化激活了 Notch 信号通路。因此，Klf5 及其乙酰化通过控制基底祖细胞的命运，有助于产后前列腺的发育和再生。
