Transcriptional and post-transcriptional control in aggressive cancer and metastasis

• Grant number: 19/17282-5
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: September 01, 2020
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Cesar Seigi Fuziwara
• Grantee: Cesar Seigi Fuziwara
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Edna Teruko Kimura ; Lin He
• Associated scholarship(s): 24/21803-9 - Effect of Hoxb7 gene editing with CRISPR/Cas9 in lung cancer metastasis, BP.IC; 24/09472-7 - The role of FOXM1 and its cross-talk with MAPK pathway and EZH2 in agressive thyroid cancer, BP.MS; 23/18041-7 - Modulation of new metastasis suppressor genes in lung cancer, BP.IC; + associated scholarships 23/14929-3 - Effect of TERT modulation in aggressive thyroid cancer, BP.MS; 23/04452-5 - Effect of EZH2/PRC2 modulation in agressive Thyroid Carcinoma, BP.DD; 23/01260-8 - Establishing a 3D culture model for analysis of invasive potential of cancer cells with modulation of EZH2, BP.IC; 22/09813-3 - Analysis of EZH2 promoter region in thyroid cancer, BP.IC; 22/03730-9 - Effect of the modulation of EZH2/PRC in lung cancer, BP.MS; 21/14494-1 - Interaction of PRC2/EZH2 complex and lncRNAs in thyroid Cancer, BP.IC; 21/01674-1 - Effect of EZH2/PRC2 modulation in agressive thyroid carcinoma, BP.MS; 20/10403-9 - Transcriptional and post-transcriptional control in aggressive cancer and metastasis, BP.JP - associated scholarships

Abstract

Metastasis is the main cause of cancer-related death, however the progress of molecular understanding did not correspond to the urgency of this disease. Thus, the investigation of new transcriptional and posttranscriptional molecular alterations is mandatory for understanding tumor heterogeneity beyond genomics. In this context, changes in miRNA expression can act as potent post-transcriptional regulators of oncogenic signaling associated with tumor aggressiveness and metastasis. Loss of miR-200 family member miRNAs (cluster miR-200c/141 and cluster miR-200b/a/429) is observed in different types of cancer, such as thyroid and lung, and is associated with poor prognosis. In our data, we observed that miR-200 is transcriptionally silenced in metastatic lung cancer and anaplastic thyroid cancer, and that miR-200 gene promoter has sites for transcription factors (TFs) silenced in metastasis. Moreover, TFs' promoter regions show PRC2/EZH2 complex binding sites suggesting the influence of chromatin compaction in TFs silencing. Thus, understanding the molecular mechanism of TFs suppression is essential to improve metastasis treatment. In this project, we propose to investigate the role of chromatin remodeling via PRC2/EZH2 complex as a regulator of TFs and miRNAs in metastasis. This study aims to establish a new line of research with potential to train new researchers and nucleate new collaborations with Brazilian and foreign centers of excellence, such as University of California Berkeley, and also consolidate the implementation of new methodologies such as CRISP, ChIP-seq, RNA-CLIP. In the end, we expect that this study will contribute to develop new therapeutical estrategies aiming to improve metastatic patients' survival. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

XUE, BIN; CHUANG, CHEN-HUA; PROSSER, HAYDN M.; FUZIWARA, CESAR SEIGI; CHAN, CLAUDIA; SAHASRABUDHE, NEIL; KUHN, MAXIMILIAN; WU, YALEI; CHEN, JINGQI; BITON, ANNE; et al. miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts. GENES & DEVELOPMENT, v. 35, n. 15-16, p. 1109+, AUG 1 2021. (19/17282-5)

HUTH, HUGO; FUZIWARA, CESAR; KIMURA, EDNA. The role of miR-200 in anaplastic thyroid cancer aggressiveness. Cancer Research, v. 83, n. 7, p. 2-pg., 2023-04-01. (21/12284-0, 19/25116-8, 19/17282-5)

PEREIRA DOS SANTOS, MARIA GABRIELA; GATTI DA SILVA, GUILHERME HENRIQUE; NAGASSE, HELDER YUDI; FUZIWARA, CESAR SEIGI; TERUKO, KIMURA EDNA; COLTRI, PATRICIA PEREIRA. hnRNP A1 and hnRNP C associate with miR-17 and miR-18 in thyroid cancer cells. FEBS OPEN BIO, v. 12, n. 6, p. 12-pg., 2022-04-24. (19/17282-5, 17/06994-9, 19/21874-5, 19/25116-8)

DE SANTA-INEZ, DANIEL CASARTELLI; FUZIWARA, CESAR SEIGI; SAITO, KELLY CRISTINA; KIMURA, EDNA TERUKO. Targeting the Highly Expressed microRNA miR-146b with CRISPR/Cas9n Gene Editing System in Thyroid Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 15, AUG 2021. (19/25116-8, 20/10403-9, 19/17282-5)

DE MELLO, DIEGO CLARO; SAITO, KELLY CRISTINA; CRISTOVAO, MARCELLA MARINGOLO; KIMURA, EDNA TERUKO; FUZIWARA, CESAR SEIGI. Modulation of EZH2 Activity Induces an Antitumoral Effect and Cell Redifferentiation in Anaplastic Thyroid Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 9, p. 22-pg., 2023-04-26. (21/01674-1, 19/25116-8, 22/09813-3, 17/01829-0, 20/10403-9, 19/17282-5)

DE MELLO, DIEGO CLARO; MENEZES, JOICE MORAES; DE OLIVEIRA, ANTONIO TARELO FREITAS; CRISTOVAO, MARCELLA MARINGOLO; KIMURA, EDNA TERUKO; FUZIWARA, CESAR SEIGI. Modulating gene expression as a strategy to investigate thyroid cancer biology. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 68, p. 13-pg., 2024-01-01. (21/01674-1, 19/17282-5, 19/25116-8, 20/10403-9, 22/09813-3, 22/03730-9, 23/14929-3)