Long non-coding RNA H19 enhances the pro-apoptotic activity of ITF2357 (a histone deacetylase inhibitor) in colorectal cancer cells

Abstract

Introduction: Long non-coding RNA H19 (lncH19) is highly expressed in colorectal cancer (CRC) and plays critical roles in tumor development, proliferation, metastasis, and drug resistance. Indeed, the expression of lncH19 usually affects the outcomes of chemo-, endocrine, and targeted therapies. ITF2357 (givinostat) is a histone deacetylase inhibitor (HDACi) that revealed a significant anti-tumor action by inducing apoptosis in different tumor models, including leukemia, melanoma, and glioblastoma. However, no data are present in the literature regarding the use of this compound for CRC treatment. Here, we investigate the role of lncH19 in ITF2357-induced apoptosis in CRC cells.Methods: The HCT-116 CRC cell line was stably silenced for H19 to investigate the role of this lncRNA in ITF2357-induced cell death. Cell viability assays and flow cytometric analyses were performed to assess the anti-proliferative and pro-apoptotic effects of ITF2357 in CRC cell lines that are silenced or not for lncH19. RT-PCR and Western blot were used to study the effects of ITF2357 on autophagy and apoptosis markers. Finally, bioinformatics analyses were used to identify miRNAs targeting pro-apoptotic factors that can be sponged by lncH19.Results: ITF2357 increased the expression levels of H19 and reduced HCT-116 cell viability, inducing apoptosis, as demonstrated by the increase in annexin-V positivity, caspase 3 cleavage, and poly (ADP-ribose) polymerase (PARP-1) degradation. Interestingly, the apoptotic effect of ITF2357 was much less evident in lncH19-silenced cells. We showed that lncH19 plays a functional role in the pro-apoptotic activity of the drug by stabilizing TP53 and its transcriptional targets, NOXA and PUMA. ITF2357 also induced autophagy in CRC cells, which was interpreted as a pro-survival response not correlated with lncH19 expression. Furthermore, ITF2357 induced apoptosis in 5-fluorouracil-resistant HCT-116 cells that express high levels of lncH19.Conclusion: This study shows that lncH19 expression contributes to ITF2357-induced apoptosis by stabilizing TP53. Overall, we suggest that lncH19 expression may be exploited to favor HDACi-induced cell death and overcome 5-fluorouracil chemoresistance.

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…This compound exhibits anti-inflammatory and immunoregulatory activity against several inflammatory diseases, type 1 diabetes and traumatic brain injury [ 215 – 218 ]. Furthermore, Givinoistat has demonstrated anti-tumor activity against hematologic malignancies and solid tumor cancers by inducing apoptosis [ 219 – 222 ]. It should be noted that Givinoistat has displayed a protective impact in managing cardiovascular diseases, as suggested by recent research studies.…”

HAMP predicts a pivotal role in modulating the malignant behaviors of non-small cell lung cancer cells

“…Long noncoding RNAs (lncRNAs) are extended noncoding RNAs that surpass 200 nucleotides and are devoid of protein-coding capability [ 11 ]. An accumulating body of data hints at the potential of lncRNAs to function as modulators in nearly every cellular process and are intricately intertwined with physiological shifts within organisms and a spectrum of disorders, encompassing malignancies [ 12 – 14 ]. The study of lung cancer-related lncRNAs is still an emerging field, and only a few lncRNAs, such as the lncRNA MALAT1 [ 15 ], the lncRNA UCA1 [ 16 ], the lncRNA HNF1A-AS1 [ 17 ], and the lncRNA PVT1 [ 18 ], have been proven to exert biological function and clinical significance.…”