Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

Wu, Maomao; Ingram, Lishann M.; Tolosa, Ezequiel J.; Vera, Renzo E.; Li, Qianjin; Kim, Sungjin; Ma, Yu; Spyropoulos, Demetri D.; Beharry, Zanna; Huang, Jiaoti; Fernández-Zapico, Martín E.; Cai, Houjian

doi:10.1074/jbc.m116.753129

Cited by 20 publications

(18 citation statements)

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“…Blockade of Shh signaling by overexpression of the Shh(C25S) mutant inhibits expression of p63 or CK5, a marker of progenitor/basal cells in prostate tissue (26,27), and prostate spheroid formation. This result is consistent with our previous experimental evidence showing that overexpression of Gli3T, a dominant-negative suppressor of Gli signaling, inhibits the renewal capacity of prostate progenitor cells (20). Our studies illustrate that the Shh-Gli2/3-p63 signal transduction pathway is essential for maintaining homeostasis of prostate stem cells in the epithelial compartment ( Fig.…”

Section: Discussionsupporting

confidence: 93%

“…S2). As reported previously (20), overexpression of Gli3T, a dominant-negative repressor of Gli signaling, in PrECs significantly inhibited primary prostate sphere formation ( Fig. 1D).…”

Section: Cell Autonomous Shh-gli Signaling Regulates the Renewal Potesupporting

confidence: 88%

“…We have demonstrated previously that epithelial Gli signaling is essential in regulating the renewal potential of prostate stem/progenitor cells (20). To further examine the role of the cell-autonomous Shh-Gli signaling axis in controlling prostate stem cell activity, lentiviral vectors overexpressing pre-Shh(WT) or the pre-Shh(C25S) mutant were constructed (Fig.…”

Section: Cell Autonomous Shh-gli Signaling Regulates the Renewal Potementioning

confidence: 99%

“…P63, CK5, and CK14 are well-established markers of prostate basal/progenitor cells, and CK8 and CK18 are known luminal markers. We have shown previously that overexpression of Gli3T and shRNA-Gli2 inhibited p63 expression (20). Therefore, we analyzed whether Shh(WT) or Shh(C25S) regulates the levels of these proteins in PEB cells, a cell line isolated from mouse prostate basal cells (23).…”

Section: Cell Autonomous Shh-gli Signaling Regulates the Renewal Potementioning

confidence: 99%

“…We have shown previously that epithelial Gli signaling regulates the expression of p63 and plays an essential role in the maintenance of the homeostasis and renewal potential of prostate stem/progenitor cells (20). Dysregulation of Gli signaling by oncogenic events, such as the synergy of Kras and androgen receptor (AR), promote the pathological expansion of basal/ progenitor cells (20,21). In this study, we demonstrate that the Shh-Gli signaling axis mediates the interaction of stromalepithelial cells in prostate tissue regeneration under physiological conditions.…”

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confidence: 99%

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Stromal Gli signaling regulates the activity and differentiation of prostate stem and progenitor cells

Alsaidan

Rai

et al. 2018

Journal of Biological Chemistry

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Interactions between cells in the stroma and epithelium facilitate prostate stem cell activity and tissue regeneration capacity. Numerous molecular signal transduction pathways, including the induction of sonic hedgehog (Shh) to activate the Gli transcription factors, are known to mediate the cross-talk of these two cellular compartments. However, the details of how these signaling pathways regulate prostate stem and progenitor cell activity remain elusive. Here we demonstrate that, although cell-autonomous epithelial Shh-Gli signaling is essential to determine the expression levels of basal cell markers and the renewal potential of epithelial stem and progenitor cells, stromal Gli signaling regulates prostate stem and progenitor cell activity by increasing the number and size of prostate spheroids Blockade of stromal Gli signaling also inhibited prostate tissue regeneration The inhibition of stromal Gli signaling suppressed the differentiation of basal and progenitor cells to luminal cells and limited prostate tubule secretory capability. Additionally, stromal cells were able to compensate for the deficiency of epithelial Shh signaling in prostate tissue regeneration. Mechanistically, suppression of Gli signaling increased the signaling factor transforming growth factor β (TGFβ) in stromal cells. Elevation of exogenous TGFβ1 levels inhibited prostate spheroid formation, suggesting that a stromal Gli-TGFβ signaling axis regulates the activity of epithelial progenitor cells. Our study illustrates that Gli signaling regulates epithelial stem cell activity and renewal potential in both epithelial and stromal compartments.

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Section: Discussionsupporting

confidence: 93%

“…S2). As reported previously (20), overexpression of Gli3T, a dominant-negative repressor of Gli signaling, in PrECs significantly inhibited primary prostate sphere formation ( Fig. 1D).…”

Section: Cell Autonomous Shh-gli Signaling Regulates the Renewal Potesupporting

confidence: 88%

Section: Cell Autonomous Shh-gli Signaling Regulates the Renewal Potementioning

confidence: 99%

Section: Cell Autonomous Shh-gli Signaling Regulates the Renewal Potementioning

confidence: 99%

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confidence: 99%

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Stromal Gli signaling regulates the activity and differentiation of prostate stem and progenitor cells

Alsaidan

Rai

et al. 2018

Journal of Biological Chemistry

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Promotion of Lung Cancer Metastasis by SIRT2‐Mediated Extracellular Protein Deacetylation

Xiong

Zhao

et al. 2022

Advanced Science

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Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post‐translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro‐environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl‐vWA domain‐carrying proteins including integrin β 3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll‐like receptor (TLR) family member TLR4 or TLR2 activation. TLR‐activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)‐mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3‐K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle‐like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.

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The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

Abstract: Edited by Eric FearonAlthough the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63

Cited by 20 publications

References 50 publications

Stromal Gli signaling regulates the activity and differentiation of prostate stem and progenitor cells

Stromal Gli signaling regulates the activity and differentiation of prostate stem and progenitor cells

Promotion of Lung Cancer Metastasis by SIRT2‐Mediated Extracellular Protein Deacetylation

The foggy world(s) of p63 isoform regulation in normal cells and cancer

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