NFκB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC)

Abstract

Cisplatin-based chemotherapy is the standard treatment of choice for head and neck squamous cell carcinoma (HNSCC). The efficiency of platinum-based therapies is directly influenced by the development of tumor resistance. Multiple signaling pathways have been linked to tumor resistance, including activation of nuclear factor kappa B (NFκB). We explore a novel mechanism by which NFκB drives HNSCC resistance through histone modifications. Post-translational modification of histones alters chromatin structure, facilitating the binding of nuclear factors that mediate DNA repair, transcription, and other processes. We found that chemoresistant HNSCC cells with active NFκB signaling respond to chemotherapy by reducing nuclear BRCA1 levels and by promoting histone deacetylation (chromatin compaction). Activation of this molecular signature resulted in impaired DNA damage repair, prolonged accumulation of histone γH2AX and increased genomic instability. We found that pharmacological induction of histone acetylation using HDAC inhibitors prevented NFκB-induced cisplatin resistance. Furthermore, silencing NFκB in HNSCC induced acetylation of tumor histones, resulting in reduced chemoresistance and increased cytotoxicity following cisplatin treatment. Collectively, these findings suggest that epigenetic modifications of HNSCC resulting from NFκB-induced histone modifications constitute a novel molecular mechanism responsible for chemoresistance in HNSCC. Therefore, targeted inhibition of HDAC may be used as a viable therapeutic strategy for disrupting tumor resistance caused by NFκB.

Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers

“…Prior studies reported that cisplatin could induce NF-κB activation in different type of cancers, which led to the drug resistance [21, 56, 57]. Interestingly, we found that cisplatin can substantially increase nuclear p65 expression and phosphorylation level as well as NF-κB DNA binding activity in HNSCC cells, and both the constitutive and cisplatin-induced NF-κB activation could be suppressed upon garcinol treatment in HNSCC cells.…”

Treatment of Head and Neck Squamous Cell Carcinoma According on the Specific Molecular Features of the Tumor (A Literature Review)

“…Эпигенетические модификации могут позволить этим клеткам адаптироваться к режимам терапии без появления новых мутаций [41]. К при-меру, установлено, что NFκB локализован в ядре при ПРГШ, где он модифицирует организацию хро-матина путем влияния на ацетилирование гистона 3, конденсируя хроматин, и уменьшает чувствительность опухолевых клеток к хроматину [42]. Таким образом, лечение с использованием ингибиторов гистоновой деацетилазы повторяет эффект ингибирования NFκB, сенсибилизируя опухолевые клетки к химиопрепара-там [41].…”

Resistência de células de carcinoma epidermóide bucal à terapia fotodinâmica mediada pelo ácido 5-aminolevulínico

“…A indução farmacológica da acetilação da histona preveniu esse fator de transcrição de induzir resistência à cisplatina. Em conjunto esses resultados indicam que o NFB promove resistência tumoral pela modulação da organização da cromatina e dos fatores acetil-histona 3 e BRCA1 (Almeida et al, 2014).…”