Abstract
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.
Highlights
Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation
Costaining total KLF5 and acetylated KLF5 (Ac-KLF5) with basal cell marker p63 and luminal cell marker CK8 demonstrated that, in human prostates, total KLF5 was detected in about 62% and Ac-KLF5 in 38% of basal cells, while total KLF5 and Ac-KLF5 were detected in ~50 and 15% of luminal cells respectively (Fig. 1a, b)
Total KLF5 is expressed in both basal and luminal cells, Ac-KLF5 is more commonly expressed in basal cells
Summary
Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation. Androgen deprivation leads to rapid apoptosis of ~90% of luminal cells and a small percentage of basal cells, and the prostate epithelium regenerates completely ~2 weeks after androgen administration[16,17] Both luminal and basal stem/progenitor cells contribute to prostate regeneration[4,10]. We apply in vitro and in vivo models to demonstrate that Klf[5] and its acetylation control the cell fate of prostatic basal progenitors to contribute to postnatal development and regeneration of prostates in part by regulating the Notch signaling
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