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.
Highlights
Kidney cancer and clear cell renal carcinoma are the 16th most common cause of death worldwide. ccRCC is often metastasized at diagnosis, and surgery remains the main treatment; early diagnosis and new therapeutic strategies are highly desirable
CPTH2 inhibits HAT activity and decreases tumor cell viability through apoptosis Papillary thyroid (K1) and clear cell Renal Cell Carcinoma cell lines were incubated with CPTH2 at the most effective concentration of 100 μM in comparison with untreated and excipient (DMSO) controls (Fig. 1)
Despite intrinsic levels of HAT activity been higher in Papillary thyroid cancer cells (K1) than in 786-O, CPTH2 treatment caused a comparable drop of the activity in both lines (Fig. 1a), according to a direct enzyme’s inhibition of the drug
Summary
Kidney 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; early diagnosis and new therapeutic strategies are highly desirable. 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. The majority of kidney cancers (70%) are classified as clear cell renal carcinoma (ccRCC), at average age of diagnosis (60–64 years) [2]. It is often metastasized [3]; identification of new therapeutic strategies is highly desirable. We found a sudden increase of H3AcK18 and KAT3B in the switch from G1 to G2 tumor grade This effect was paired by a progressive decrease of H3AcK14 levels. This analysis suggests a novel approach and identifies promising prognosticators in clear cell carcinoma
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