Таргетирование комплекса ремоделирования хроматина SWI/SNF в терапии онкологических заболеваний

Ремоделирование хроматина является одним из основных эпигенетических путей регуляции экспрессии генов как в норме, так и при онкологических заболеваниях. Гены, кодирующие белковые субъединицы комплексов ремоде­лирования sWI/sNF, часто мутируют и/или изменяют свою экспрессию в опухолях человека, влияя на программу экспрессии многих генов при канцерогенезе, что связано с возникновением и прогрессированием рака. Сегодня не существует терапевтических препаратов, которые бы непосредственно изменяли структуру хроматина, посколь­ку этот комплексный процесс требует привлечения большого количества генов, белков, некодирующих транскриптов и других молекул-посредников. Тем не менее воздействие на комплексы ремоделирования хроматина можно про­водить, последовательно влияя на субъединицы и кодирующие их гены, а также некодирующие РНк, которые регу­лируют работу данных комплексов и направляют их в районы генов-мишеней. предложены несколько успешных стратегий воздействия на эпигенетические регуляторы, связанные с хроматином, чтобы вызвать синтетическую летальность опухолевых клеток и блокировать опухолевый рост. для воздействия на процессы ремоделирования хроматина исследуют различные стратегии и механизмы: от ингибиторов бромодоменов отдельных субъединиц до прямого воздействия на функцию sWI/sNF посредством разрушения его основной субъединицы аденозинтри­фосфатазы.
В обзоре подробно проанализированы пути и механизмы воздействия на комплекс ремоделирования хроматина sWI/sNF (от экспериментов на опухолевых клетках и модельных животных до сочетанного использования клини­ческих препаратов для лечения онкологических пациентов) с целью получения стойкого противоопухолевого эф­фекта.

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