2018
DOI: 10.15252/emmm.201708478
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Dual inhibition of AKT ‐m TOR and AR signaling by targeting HDAC 3 in PTEN ‐ or SPOP ‐mutated prostate cancer

Abstract: AKT‐mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetyla… Show more

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Cited by 46 publications
(18 citation statements)
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References 72 publications
(120 reference statements)
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“…Furthermore, in addition to STAT1 signalling, acetylationphosphorylation switch has also been observed in other pathways such as AKT signalling (Yan et al, 2018) and Tau aggregation (Carlomagno et al, 2017). However, only Class I and Class II HDACs have been shown to be implicated in this phenomenon (Carlomagno et al, 2017;Krämer & Heinzel, 2010;Yan et al, 2018). In agreement with this, we earlier showed that IAV-induced phosphorylation of FIGURE 6 IFNα-induced phosphorylation of STAT1 and expression of ISG15, IFITM3, and viperin is delayed in HDAC11-depleted cells.…”
Section: Discussionsupporting
confidence: 69%
See 1 more Smart Citation
“…Furthermore, in addition to STAT1 signalling, acetylationphosphorylation switch has also been observed in other pathways such as AKT signalling (Yan et al, 2018) and Tau aggregation (Carlomagno et al, 2017). However, only Class I and Class II HDACs have been shown to be implicated in this phenomenon (Carlomagno et al, 2017;Krämer & Heinzel, 2010;Yan et al, 2018). In agreement with this, we earlier showed that IAV-induced phosphorylation of FIGURE 6 IFNα-induced phosphorylation of STAT1 and expression of ISG15, IFITM3, and viperin is delayed in HDAC11-depleted cells.…”
Section: Discussionsupporting
confidence: 69%
“…This phenomenon is characterised by the acetylation of STAT1 counteracting its phosphorylation to affect downstream target gene expression (Krämer et al, 2009). Furthermore, in addition to STAT1 signalling, acetylationphosphorylation switch has also been observed in other pathways such as AKT signalling (Yan et al, 2018) and Tau aggregation (Carlomagno et al, 2017). However, only Class I and Class II HDACs have been shown to be implicated in this phenomenon (Carlomagno et al, 2017;Krämer & Heinzel, 2010;Yan et al, 2018).…”
Section: Discussionmentioning
confidence: 99%
“…pAkt expression may, therefore, depend on the drug exposure time. Yan et al has observed reduced pAkt expression in the presence of SAHA or panobinostat [ 60 ]. However, their results stem from the use of C4-2 cells, which are androgen receptor-positive, whereas PC3 cells are not.…”
Section: Discussionmentioning
confidence: 99%
“…Another group investigated the efficacy of epigenetic related drugs on SPOP mutant tumors. In 2018 Yan et al publish that HDAC3 inhibitors blocked mTOR/AKT and AR signaling in tumors harboring SPOP mutations 74 .…”
Section: Spop Clinical Impactmentioning
confidence: 99%