Linking Transcription Factors Turns Cancer Drivers into Cancer Killers

Linking Transcription Factors Turns Cancer Drivers into Cancer Killers

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What if you could turn a cancer cell against itself? In a remarkable recent paper, a team of researchers used the intrinsic properties of a cancer driver protein that suppresses cell death to make it activate cell death instead. This approach, which uses translational/epigenetic chemical inducers of proximity (TCIPs), can potentially be applied to therapeutic applications beyond cancer as well.

The Role of Proximity in Molecular Biology

Receptor function, epigenetic regulation, regulation of transcription, and post-translational modifications: these are all biological processes that require key molecules to be in close proximity to function. The many biochemical binding events that occur in cells do not occur randomly, but by induced proximity, or the bringing together of two molecules to interact.

The importance of induced proximity has been studied using chemical inducers of proximity, known as CIPs. In a recent Nature paper, Gourisankar et al. explored the idea that CIPs could be used to link distinct cellular processes – artificially inducing proximity between two molecules that would otherwise not meet to activate a new process.

Linking CIPs to Cancer Drivers Activates Cancer Cell Death

It is well known that cancer cells possess the ability to suppress the activation of pro-apoptosis (cell death) genes, while simultaneously increasing the activation of growth-related genes. Could these cancer-driving processes be linked to instead activate pathways of cell death?

The authors produced a new class of CIPs called transcriptional/epigenetic CIPs (TCIPs) that link cancer drivers to the promoters of cell death genes, thereby using the presence of the cancer driver to activate an irreversible cell death program. This was done in a model of diffuse B cell lymphoma, where the transcription factor BCL6 is severely deregulated. In this type of lymphoma, BCL6 binds to the promoters of cell death genes and epigenetically silences their expression.

The authors used their most potent TCIP, TCIP1, to covalently link BCL6 to a molecule that promotes overall transcription in cancer cells called BRD4. These covalently linked transcription factors were recruited to the promoters of cell death genes, but instead of BCL6 being able to bind to the promoter and silence gene expression, the linked proteins induced expression of the cell death proteins, activating apoptosis and killing the cancer cells.

Future Therapeutic Applications of TCIPs

TCIP1 was able to effectively kill diffuse B cell lymphoma cell lines, including chemotherapy-resistant cell lines, with high specificity. Though it is a long way from a functional drug, this proof-of-concept of TCIPs opens up exciting avenues for research not just in cancer therapeutics, but in a number of developmental and regenerative medicine applications where silenced genes need to be re-activated. By harnessing the intrinsic properties of the cancer cell, these researchers were able to “flip the switch” from cancerous growth to death of cancer cells.

Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help

Groundbreaking studies like these are made possible by technological advances making biological data generation, storage and analysis faster and more accessible than ever before. From pipeline development and software engineering to deploying existing bioinformatics tools, Bridge Informatics can help you on every step of your research journey.

As experts across data types from leading sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing and interpreting genomic and transcriptomic data. Bridge Informatics’ bioinformaticians are trained bench biologists, so they understand the biological questions driving your computational analysis. Click here to schedule a free introductory call with a member of our team.

Jane Cook, Biochemist & Content Writer, Bridge Informatics

Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].

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