Transcriptional and post-transcriptional control in aggressive cancer and metastasis

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)