KAT3B-p300 and H3AcK18/H3AcK14 levels are prognostic markers for kidney ccRCC tumor aggressiveness and target of KAT inhibitor CPTH2

Abstract

BackgroundKidney cancer and clear cell renal carcinoma (ccRCC) are the 16th most common cause of death worldwide. ccRCC is often metastasized at diagnosis, and surgery remains the main treatment; therefore, early diagnosis and new therapeutic strategies are highly desirable. KAT inhibitor CPTH2 lowers histone H3 acetylation and induces apoptosis in colon cancer and cultured cerebellar granule neurons. In this study, we have evaluated the effects of CPTH2 on ccRCC 786-O cell line and analyzed drug targets expressed in ccRCC tumor tissues at different grade.ResultsCPTH2 decreases cell viability, adhesion, and invasiveness in ccRCC cell line 786-O. It shows preferential inhibition for KAT3B-p300 with hypoacetilating effects on histone H3 at specific H3-K18. Immunohistochemical analysis of 70 ccRCC tumor tissues compared with peritumoral normal epithelium showed a statistical significant reduction of p300/H3AcK18 paralleled by an increase of H3AcK14 in G1 grade and an opposed trend during tumor progression to worst grades. In this study, we demonstrate that these marks are CPTH2 targets and significative prognosticators of low-grade ccRCC tumor.ConclusionsccRCC is substantially insensitive to current therapies, and the efficacy of clinical treatment is dependent on the dissemination stage of the tumor. The present study shows that CPTH2 is able to induce apoptosis and decrease the invasiveness of a ccRCC cell line through the inhibition of KAT3B. In a tumor tissue analysis, we identified new prognosticator marks in grade G1 ccRCC tumors. Low KAT3B/H3AcK18 vs. high H3AcK14 were found in G1 while an opposed trend characterized tumor progression to worst grades. Our collected results suggest that CPTH2 reducing KAT3B and H3AcK18 can be considered a promising candidate for counteracting the progression of ccRCC tumors.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0473-4) contains supplementary material, which is available to authorized users.

A Histone Acetyltransferase Inhibitor with Antifungal Activity against CTG clade Candida Species

“…Furthermore, histone H3 acetylation is unchanged upon treatment with inhibitory concentrations of CPTH2. These data are in line with previous reports showing that CPTH2 does not only inhibit Gcn5, but also has other targets as well [19,22,23,24]. In S. cerevisiae deletion of GCN5 also increases the susceptibility to CPTH2, albeit at much higher concentrations compared to CTG clade Candida species [19,22].…”

“…In S. cerevisiae deletion of GCN5 also increases the susceptibility to CPTH2, albeit at much higher concentrations compared to CTG clade Candida species [19,22]. Furthermore, in mammalian systems CPTH2 or its derivatives have been shown to also inhibit the HATs p300 and NAT10 [23,24]. Based on its conserved target site H3K56 and on structural similarities, the fungal-specific Rtt109 HAT has been identified as an orthologue of p300 [25].…”

LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer

“…H3K27ac-induced lncRNA EIF3J-AS1 overexpression has been suggested to accelerate proliferation and impede apoptosis of CC cells [ 18 ]. As another major component of the complex, EP300 (also termed as KAT3B or p300) is predictive of worse prognosis in human malignancies, such as prostate, liver, kidney, and breast cancer [ 19 ]. Under the condition of oral squamous cell carcinoma, EP300 activated LINC00941 transcription through upregulating H3K27ac modification in its promoter [ 20 ].…”

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

“…Because lysine acetylation is mostly regulated by acetyltransferases and deacetylases, we used GPS-PAIL 2.0 software to make simple predictions for the seven acetyltransferases of the differentially acetylated proteins we quantified. Previous studies have shown that the down-regulation of acetyltransferase KAT3B induces apoptosis in renal carcinoma and the variations in the expression levels of MYSTI/MOF/KAT8 may affect the cell cycle and the EGFR signaling pathway ( Cocco et al, 2018 ; Dong et al, 2019 ). Additionally, our prediction results identified certain acetyltransferases with high scores, such as KAT8 which can act on Parp2 (K36/K51 site) and Casp3 (K25 site).…”