Modulation of EZH2 Activity Induces an Antitumoral Effect and Cell Redifferentiation in Anaplastic Thyroid Cancer

Autor(es)

de Mello, Diego Claro ; Saito, Kelly Cristina ; Cristovao, Marcella Maringolo ; Kimura, Edna Teruko ; Fuziwara, Cesar Seigi

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 24, n. 9, p. 22-pg., 2023-04-26.

Resumo

Anaplastic thyroid cancer (ATC) is a rare and lethal form of thyroid cancer that requires urgent investigation of new molecular targets involved in its aggressive biology. In this context, the overactivation of Polycomb Repressive Complex 2/EZH2, which induces chromatin compaction, is frequently observed in aggressive solid tumors, making the EZH2 methyltransferase a potential target for treatment. However, the deregulation of chromatin accessibility is yet not fully investigated in thyroid cancer. In this study, EZH2 expression was modulated by CRISPR/Cas9-mediated gene editing and pharmacologically inhibited with EZH2 inhibitor EPZ6438 alone or in combination with the MAPK inhibitor U0126. The results showed that CRISPR/Cas9-induced EZH2 gene editing reduced cell growth, migration and invasion in vitro and resulted in a 90% reduction in tumor growth when EZH2-edited cells were injected into an immunocompromised mouse model. Immunohistochemistry analysis of the tumors revealed reduced tumor cell proliferation and less recruitment of cancer-associated fibroblasts in the EZH2-edited tumors compared to the control tumors. Moreover, EZH2 inhibition induced thyroid-differentiation genes' expression and mesenchymal-to-epithelial transition (MET) in ATC cells. Thus, this study shows that targeting EZH2 could be a promising neoadjuvant treatment for ATC, as it promotes antitumoral effects in vitro and in vivo and induces cell differentiation. (AU)

• Processo FAPESP: 21/01674-1 - Efeito da modulação de EZH2/PRC2 no câncer de tiroide agressivo
• Beneficiário: Diego Claro de Mello
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 19/25116-8 - Modulação de microRNAs e sua rede regulatória de alvos com potencial terapêutico no câncer de tiroide: aplicação da edição gênica com CRISPR/Cas9
• Beneficiário: Edna Teruko Kimura
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 22/09813-3 - Análise da região promotora de EZH2 no câncer de tiroide
• Beneficiário: Marcella Maringolo Cristovão
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 17/01829-0 - Estudo do papel dos microRNAs na metástase através de modelos de camundongos geneticamente modificados
• Beneficiário: Cesar Seigi Fuziwara
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 20/10403-9 - Controle transcricional e pós-transcricional no câncer agressivo e metástase
• Beneficiário: Cesar Seigi Fuziwara
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• Processo FAPESP: 19/17282-5 - Controle transcricional e pós-transcricional no câncer agressivo e metástase
• Beneficiário: Cesar Seigi Fuziwara
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores