Transcriptional control of cancer metastasis

Abstract

Transcriptional regulation is an essential component of tumor progression and metastasis. During cancer progression, dysregulation of oncogenic or tumor-suppressive transcription factors (TFs), as well as master cell fate regulators and tumor microenvironment-induced factors, collectively influence multiple steps of the metastasis cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Furthermore, epigenetic alterations in tumor cells, including DNA methylation, as well as activation or suppression of histone deacetylases (HDACs), histone acetyltransferases (HATs), and other chromatin-modifying enzymes, can further distort the transcriptional network to influence metastasis. We focus here on recent research advances in transcriptional control of metastasis and highlight the therapeutic potential of targeting such transcriptional regulatory networks.

Keywords: epigenetics; epithelial–mesenchymal transition; metastasis; transcription factors; tumor microenvironment.

Figure 1

Transcription factors contribute to every stage of metastasis. The upregulation (Red), downregulation (Green), or gain of function mutations (Orange) in individual transcription factors represent important events during metastatic progression. Altered TF expression mediates early events in metastatic progression, including cell fate (mis)regulation, inflammation, and the response to hypoxic conditions. Additional TFs can regulate EMT, invasion through surrounding tissues, and intravasation, as well as survival in circulation and the eventual colonization at distant sites. It is possible for individual transcription factors to regulate multiple steps during the metastatic cascade, such as TGF-β, which regulates EMT, inflammation, survival in circulation, and colonization at distant organs.

Figure 2

Transcriptional regulatory pathways surrounding the p53-miR-34a-SIRT1 axis. p53 can activate multiple downstream components, including miRNAs such as miR-34a, leading to cellular arrest or apoptosis. Activation of miR-34a inhibits EMT by antagonizing Snail1 expression, while simultaneously inhibiting SIRT1. SIRT1 is capable of enhancing EMT through the repression of CDH1, but is also able to inhibit acetylated and activated p53. Thus, the p53–mediated repression of miR-34a leads to a positive feedback loop via the repression of SIRT1.