New research highlights the critical role of CBFB in suppressing tumor growth by coordinating transcription and translation processes

A groundbreaking study published in Nature Communications has uncovered a novel role for the transcription factor CBFB in regulating the processes of translation and transcription in the context of breast cancer, offering fresh insights into potential therapeutic strategies. This pivotal research, led by an accomplished team from the National Cancer Institute (NCI) at the National Institutes of Health (NIH), has revealed a dual role for CBFB in orchestrating the defense against the onset and progression of tumors.

DOI: 10.1038/s41467-019-10102-6

Abstract

The transcription factor CBFB is a master regulator of gene expression, previously known to be highly mutated in a variety of human cancers, including breast cancer. CBFB traditionally functions as a transcriptional regulator, exerting control over the expression of genes critical for cellular function. However, scientists at the NCI have discovered that besides its known role, CBFB also plays an unexpected part in controlling the translation of proteins.

In the cited study, deep sequencing (RIP-seq) revealed that cytoplasmic CBFB binds to and regulates the translation of numerous messenger RNA (mRNA) transcripts. The research team observed that CBFB interacts with these mRNAs through heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhances translation by associating with eukaryotic initiation factor 4B (eIF4B). Notably, this interaction also impacts the translation of RUNX1 mRNA, coding for the transcriptional partner of CBFB, thereby influencing its own regulatory complex.

Additionally, nuclear CBFB, in partnership with RUNX1, was found to suppress the oncogenic NOTCH signaling pathway in breast cancer, further highlighting CBFB’s role in cancer defense.

The Dual Function of CBFB

The findings of the Malik Navdeep N et al. study underscore CBFB’s role as both a suppressor of breast cancer and a coordinator of genetic processes. Traditionally, different factors modulated translation and transcription. This paradigm shifted with the revelation that CBFB could bind RNA in the cytoplasm and regulate the production of proteins through its interaction with the translation machinery.

Such a mechanism is vital in the suppression of cancer, wherein the dysregulation of both transcription and translation is common. The discovery that CBFB oversees these intertwined pathways offers a molecular explanation for how certain cancer cells may bypass critical cellular surveillance systems. By influencing both mRNA translation and transcription repression, CBFB serves as a double-layered defense mechanism against tumor progression.

Clinical Implications

Navdeep N and collaborators have opened the door to potential new therapeutic avenues for breast cancer. Their study proffers CBFB as a pivotal element in both the regulation of gene expression and protein synthesis, making it a promising target for drug development.

The intricate role of CBFB may lead researchers and clinicians to develop treatments that specifically reinforce its function, restore its activity when mutated, or mimic its action when downregulated in cancerous cells. Potent inhibitors or modulators of the pathways influenced by CBFB could provide valuable tools in combating breast cancer.

The Research Continues

The team at the NCI is committed to advancing our understanding of breast cancer biology, with ongoing investigations into the interplay between CBFB and other molecular players. New studies focus on exploring how restoring normal CBFB function could thwart cancer growth and whether other cancers are similarly affected by changes in CBFB-mediated translational and transcriptional control.

Keywords

1. CBFB Function in Cancer
2. Breast Cancer Transcription Factors
3. Protein Translation Regulation
4. CBFB and NOTCH Signaling Pathway
5. CBFB Mutation and Breast Cancer

References

1. Nature Communications
Malik Navdeep N et al. (2019). The transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription. Nat Commun, 10(1), 2071. DOI: 10.1038/s41467-019-10102-6

2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013.

3. Bhat M, et al. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 2015;14:261–278. doi: 10.1038/nrd4505.

4. Tahmasebi S, Khoutorsky A, Mathews MB, Sonenberg N. Translation deregulation in human disease. Nat. Rev. Mol. Cell Biol. 2018;19:791–807. doi: 10.1038/s41580-018-0034-x.

5. Kapadia B, et al. Fatty acid synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL. Nat. Commun. 2018;9:829. doi: 10.1038/s41467-018-03028-y.

Conclusion

This NCI-led study has shone a light on CBFB as a dual-action transcription factor, far exceeding its known transcriptional regulation roles. By uncovering a symbiotic relationship between CBFB’s two regulatory functions, this research has the potential to offer significant advancements in breast cancer therapy and prognosis. As a suppressor of breast cancer, CBFB now symbolizes an essential target in future oncological research with the promise of improving the lives of millions affected by this disease.