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

Author(s)

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

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 24, n. 9, p. 22-pg., 2023-04-26.

Abstract

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)

• FAPESP's process: 21/01674-1 - Effect of EZH2/PRC2 modulation in agressive thyroid carcinoma
• Grantee: Diego Claro de Mello
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/25116-8 - Modulation of microRNAs and its regulatory target network with therapeutic potential in thyroid cancer: application of gene editing with CRISPR/Cas9
• Grantee: Edna Teruko Kimura
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/09813-3 - Analysis of EZH2 promoter region in thyroid cancer
• Grantee: Marcella Maringolo Cristovão
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/01829-0 - Study the role of microRNA in cancer metastasis using genetically engineered mouse models
• Grantee: Cesar Seigi Fuziwara
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 20/10403-9 - Transcriptional and post-transcriptional control in aggressive cancer and metastasis
• Grantee: Cesar Seigi Fuziwara
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 19/17282-5 - Transcriptional and post-transcriptional control in aggressive cancer and metastasis
• Grantee: Cesar Seigi Fuziwara
• Support Opportunities: Research Grants - Young Investigators Grants