Klf5 acetylation regulates luminal differentiation of basal progenitors in prostate development and regeneration

Zhang, Baotong; Ci, Xinpei; Tao, Ran; Ni, Jianping Jenny; Xing, Xuan; King, Jamie; Xia, Siyuan; Li, Yixiang; Frierson, Henry F.; Lee, Dong Kee; Xu, Jianming; Osunkoya, Adeboye O.; Dong, Jin Tang

doi:10.1038/s41467-020-14737-8

Cited by 31 publications

(26 citation statements)

References 52 publications

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“…In mouse prostates, castration-mediated androgen depletion increased Klf5-positive cells [29], which is seemingly inconsistent with the induction of KLF5 by androgen in PCa cells (Figure 1). Compared to luminal cells in the prostate, basal cells preferentially express Klf5, particularly acetylated Klf5 [30], castration causes massive death in luminal cells but much less so in basal cells, and basal cells express much less AR and are androgen insensitive. LNCaP and C4-2B cells are AR-positive and androgen-dependent/sensitive, and thus have a different lineage from basal cells.…”

Section: Discussionmentioning

confidence: 99%

KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

Zhang

Liu

et al. 2020

Cancers

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Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

Zhang

Liu

et al. 2020

Cancers

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“…A sphere formation assay was performed as previously described by Zhang et al (39) with slight modification. Falcon 8-well chamber slides (product no.…”

Section: Sphere Formation Assaymentioning

confidence: 99%

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Lee

Zafar

et al. 2021

Oncol Rep

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Studies on cultured cancer cells or cell lines have revealed multiple acid extrusion mechanisms and their involvement in cancer cell growth and progression. In the present study, the role of the sodium bicarbonate transporters (NBCs) in prostate cancer cell proliferation and viability was examined. qPCR revealed heterogeneous expression of five NBC isoforms in human prostate cancer cell lines LNCaP, PC3, 22RV1, C4-2, DU145, and the prostate cell line RWPE-1. In fluorescence pH measurement of LNCaP cells, which predominantly express NBCe1, Na + and HCO 3 --mediated acid extrusion was identified by bath ion replacement and sensitivity to the NBC inhibitor S0859. NBCe1 knockdown using siRNA oligonucleotides decreased the number of viable cells, and pharmacological inhibition with S0859 (50 µM) resulted in a similar decrease. NBCe1 knockdown and inhibition also increased cell death, but this effect was small and slow. In PC3 cells, which express all NBC isoforms, NBCe1 knockdown decreased viable cell number and increased cell death. The effects of NBCe1 knockdown were comparable to those by S0859, indicating that NBCe1 among NBCs primarily contributes to PC3 cell proliferation and viability. S0859 inhibition also decreased the formation of cell spheres in 3D cultures. Immunohistochemistry of human prostate cancer tissue microarrays revealed NBCe1 localization to the glandular epithelial cells in prostate tissue and robust expression in acinar and duct adenocarcinoma. In conclusion, our study demonstrates that NBCe1 regulates acid extrusion in prostate cancer cells and inhibiting or abolishing this transporter decreases cancer cell proliferation.

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“…Our previous studies have demonstrated that TGF-β induces the acetylation of transcription factor Krüppel-like factor 5 (KLF5) at lysine 369 (K369) via SMAD-recruited p300 acetylase 38,39 , and acetylated KLF5 (Ac-KLF5) then forms a transcriptional complex different from that of deacetylated KLF5 (deAc-KLF5), which reverses the functions of deAc-KLF5 and is essential for TGF-β to function in gene regulation, cell proliferation, differentiation, and tumorigenesis [38][39][40][41][42] . Considering the established TGF-β/Ac-KLF5 signaling axis and the function of TGF-β in the induction of EMT, bone metastases, and chemoresistance, we hypothesize that Ac-KLF5 plays a crucial role in the development of chemoresistant bone metastases in PCa.…”

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confidence: 99%

Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer

Zhang

et al. 2021

Nat Commun

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Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.

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Klf5 acetylation regulates luminal differentiation of basal progenitors in prostate development and regeneration

Cited by 31 publications

References 52 publications

KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer

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