A mounting body of evidence is uncovering how the polycomb group (PcG) proteins play a key role in the initiation, development, and progression of cancer in humans.
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Due to their function in regulating various developmental and physiological processes within human cells, their deregulation and dysfunction have been linked with processes associated with cancer, such as apoptosis inhibition, cellular proliferation enhancement, inappropriate activation of developmental pathways, and the increase of cancer stem cell population. They have also been found to manage different oncogenes and tumor suppressor genes, and studies have shown that they are related to survival rates of those with cancer.
New research is elucidating their potential function as a biomarker of cancer, as well as a molecular target for new cancer therapies.
What are PcG proteins
The polycomb group (PcG) proteins were first identified through their role as epigenetic transcriptional repressors of homeotic gene expression in fruit flies. Over the years, scientific research has found that polycomb proteins are essential to numerous biological processes that occur during the development of a human embryo. They have been seen to be fundamental in cell fate and lineage decisions, stem cell function, cellular memory, and homeostasis of tissue.
In addition, it has been found that a diverse set of genes that have roles in encoding transcription factors, signaling proteins, receptors, and morphogens, as well as encoding regulators that are key to developmental pathways.
As well as uncovering the function of polycomb proteins, extensive research has recognized the link between deregulation of these proteins and their functions and cancer. Studies have shown that their failure function normally inhibits tumor suppressors through impaired signaling, which also leads to proto-oncogenes being incorrectly activated.
PcG proteins and cancer
Studies have shown that several types of cancer in humans are associated with the deregulation of expression and function of the polycomb group proteins. When these proteins fail to function normally, adverse effects such as loss of cell identity, resistance to cell death mechanisms, increased migratory/invasive potential, and bypass of cellular senescence programs endure.
The role of the polycomb group proteins is complex, and research has uncovered a variety of pathways between their deregulation and cancer.
PcG deregulation in human cancer
Research has been able to identify specific polycomb group proteins that are deregulated in certain cancers. Abnormal levels of various proteins have been linked with different cancer types. For example, it is now accepted that in both human leukemia and solid tumors, patients express elevated levels of the BMI1 protein. An over-expression of EZH2, SUZ12, and PCL3/PHF19 is also implicated in a number of human cancers. In particular, the Ezh2 gene has been found to be amplified in the majority of hormone-refractory prostate cancers.
Further to this, research has uncovered that polycomb group protein mutations and chromosomal translocations are also related to human cancer. B cell lymphomas, follicular lymphomas, and myelodysplastic and myeloproliferative disorders have been linked with mutations and deletions of EZH2, which have the impact of inactivating its methyltransferase activity. In addition, it has been discovered that recurrent chromosomal rearrangements that are characteristic of some cancers are related to specific polycomb group proteins.
PcG proteins in cancer development and progression
The polycomb group protein known as BMI1 is implicated at the beginning of cancer development and progression. One of the functions of BMI1 is promoting B- and T-cell lymphomas through working with c-Myc. BMI1 represses the cyclin-dependent kinase inhibitor, resulting in inhibition of Myc-induced apoptosis.
In addition, other polycomb group proteins, such as EZH2 and SUZ12, have also been implicated in tumorigenesis. The initiation of the growth of cancerous cells is considered to involve transcriptional repression of the INK4b-ARF-INK4a locus, which is overseen by these polycomb group proteins.
Epigenetic deregulation
Research into a variety of cancer types has confirmed that inactivation of tumor suppressor genes through DNA hypermethylation is a key attributing factor to cancer development. Ovarian cancer, follicular lymphoma, and glioblastoma multiforme have all been linked with polycomb group target methylation. In addition, colon or prostate cancers have been linked with hypermethylated genes that are pre-marked by polycomb group proteins.
Numerous studies have been able to attribute this link to the regulatory role polycomb group proteins have on cell fate and lineage. Gradual de novo DNA methylation of polycomb group proteins targets have the impact of converting cells into an undifferentiated state, and it’s this which predisposes them to malignant transformation.
Diagnostic and prognostic biomarkers for cancer
Certain polycomb group proteins have been identified as potential diagnostic and/or prognostic biomarkers for human cancers. A number of cancers have shown an up-regulation of EZH2. Breast and prostate cancers are particularly linked with this protein. In addition, elevated expression of BMI1 has been found to be reliable at predicting both advanced disease and poor prognosis in numerous types of cancer.
Cancer prevention and therapy
Certain polycomb group proteins, such as EZH2 and BMI1, have been identified as oncogenes and cancer stem cell markers. This makes them potential targets for prevention and therapy of cancer.
Research has found that cancer stem cells have the capacity to self-renew themselves, which is key to the initiation of tumors. It also plays a role in the failure of treatment to wipe out cancer cells completely. BMI1, EZH2, and SUZ12 are all polycomb group proteins that have been implicated in the promotion of stem cells in various cancer types.
Scientists have suggested that these particular proteins could be targeted by pharmacological or genetic treatments, helping to improve treatment outcomes for cancer. However, the research is still in its infancy, and much more work is still on the horizon before we may reach established therapies.
Sources
- Chan, H. and Morey, L. (2019). Emerging Roles for Polycomb-Group Proteins in Stem Cells and Cancer. Trends in Biochemical Sciences, 44(8), pp.688-700. www.cell.com/.../S0968-0004(19)30085-4
- Scelfo, A., Piunti, A. and Pasini, D. (2014). The controversial role of the Polycomb group proteins in transcription and cancer: how much do we not understand Polycomb proteins?. FEBS Journal, 282(9), pp.1703-1722. https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.13112
- Wang, W., Qin, J., Voruganti, S., Nag, S., Zhou, J. and Zhang, R. (2015). Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications. Medicinal Research Reviews, 35(6), pp.1220-1267. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718713/
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