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Sakshi Dhavale
Did you know that pancreatic cancer has the highest mortality rate among all the major cancers? Because of this, researchers are rigorously working to find a cure for this deadly cancer type. Pancreatic Ductal Adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly lethal due to a lack of early diagnosis and a lack of response to the current treatments. But now, a set of new molecules that promote the growth of PDAC tumours has been found. These tumour-promoting agents are known as ‘Super Enhancers’.
What are Super Enhancers? How are they important?
Enhancers are sections of DNA that, when bound to certain proteins called transcription binding factors, boost the expression of genes leading to high levels of genes’ protein products. Super enhancers (SE) are a large collection of enhancers with remarkable transcription binding factors that are known to activate multiple genes simultaneously. They are highly cell-type specific and are associated with defining the identity and function of particular cell types. Studying the super-enhancers and their associated genes can shed some light on a new form of treatment which includes inhibition of the regulatory SE or the inhibition of transcription binding factors such as the RNA binding proteins (RBPs) which are associated with PDAC tumour growth.
So what does a RNA-binding protein (RBP) do? RNA-binding proteins (RBPs) are a distinct class of proteins that associate with RNA molecules to control various aspects of RNA metabolism, including RNA processing, transport, stability, and translation. They are known to have therapeutic potential for cancer, explicitly in MYC-directed tumours. MYC-directed tumours are those in which MYC-gene is either overexpressed or mutated, leading to uncontrolled cell growth and division. Some pancreatic cancers exhibit MYC amplification or overexpression, which is associated with a more aggressive disease phenotype such as pancreatic ductal adenocarcinoma. With RBPs, the potential target proteins can be studied, and using this information makes it easier to monitor the cancer’s progression, allowing early diagnosis.
SE-mediated RNA Binding Protein (RBP) cascade:
The Myc-coordinated network that is controlled by SE regulation, which helps the cancer cells by improving protein production through an increase in the generation of ribosomes. This chain of events involves a post-transcriptional agent called heterogeneous nuclear ribonucleoprotein F (hnRNP F), which plays a role in maintaining the stability of protein arginine methyltransferase 1 (Prmt1). Prmt1, in turn, modifies ubiquitin-associated protein 2-like (Ubap2l), an RNA-binding protein (RBP) directly involved in controlling translation (protein production), affecting its ability to bind to RNA molecules.
The described pathway illustrates how cancer cells can manipulate their internal processes to sustain rapid growth and division. By enhancing protein production through ribosome generation and post-transcriptional regulation, cancer cells can promote the synthesis of proteins such as hnRNP F, Prmt1and Ubap2l that support tumour development and progression. Understanding these complex regulatory networks at the molecular level is important in cancer research because it may lead to the identification of potential therapeutic targets for cancer treatment. By disrupting key points in such pathways, researchers aim to develop strategies to slow down or inhibit cancer cell growth.
- SE- HNRNPF gene complex:
In their research, when examining human pancreatic cancer cell lines, the study identified numerous genes connected to super-enhancers (SEs) involved in processes that are disturbed in cancer and are typically lower in normal cell lines. Among the top 25 genes related to super-enhancers, they found the hnRNP F gene, which plays a role in regulating alternative splicing, polyadenylation, and RNA stability. Notably, the hnRNP F protein was found to be elevated in the epithelial tumours of both early and late-stage pancreatic ductal adenocarcinoma (PDAC) when compared to normal ducts. This finding shows the significance of hnRNP F in the observed cell.
- HNRNP F-based mediation of PRMT 1:
While investigating the role of hnRNP F in regulating the growth of tumour cells, researchers identified the RNA molecules that interact with hnRNP F in human pancreatic ductal adenocarcinoma (PDAC) cells. Among the downstream targets of hnRNP F, they found PRMT1 (Protein Arginine Methyltransferase 1) which showed properties to enhance mRNA translation. To support this finding, they created a knockout gene for hnRNP F, which resulted in a 30% decrease in Prmt1 mRNA levels, and a subsequent 40% reduction in protein levels. Notably, this knockout did not impact the splicing of Prmt1 but instead played a role in stabilising the Prmt1 Transcripts. Finally, by reintroducing a functional Prmt1 transcript, the researchers were able to rescue the proliferation defect observed in Hnrnpf knockout cells. This highlights the significance of PRMT1 as a downstream target of HNRNPF in regulating cell proliferation.
- Modification of UBAP2L:
To understand the Prmt1 effect on tumour growth, deletion of Prmt1 was made. This led to a significant drop in protein production compared to the one with Prmt1. Further, a specific type of protein modification called asymmetric arginine dimethylation was studied to understand the Prmt1 role in protein production, they then examined the proteins affected by this change and found that many of them were related to a protein called Ubap2l, which is known to play a crucial role in controlling protein production. Researchers found that Ubap2l affects the expression of ribosomal RNA (rRNA) and ribosomal proteins, leading to a significant reduction in ribosome biogenesis and, hence, global translation in tumour cells.
In summary, it can be concluded that Prmt1 carries out asymmetric dimethylation of Ubap2l, this means that in a protein, one instance of a particular amino acid may be methylated, while the other may not. This type of protein modification can have significant effects on protein function and interactions. Methylation of specific amino acids in proteins can influence their binding to other molecules, cellular localization, and activity. Thereby, regulating the expression of rRNA and ribosomal proteins. This intricate regulatory process ultimately controls the translation of proteins within the context of tumour development.
A Peek into the Future: Early Diagnosis and Targeted Therapies:
The traditional route of targeting well-known oncogenic drivers like Myc and KRAS in pancreatic ductal adenocarcinoma (PDAC) has proven to be an uphill battle. We can address cancer’s complex progression by exploring a different treatment approach. This involves uncovering how genes are regulated through epigenetic changes as cancer develops. These changes act as switches for genes. Furthermore, we seek to understand the subsequent series of events and molecular changes, known as downstream processes, triggered by these initial genetic and epigenetic alterations. By focusing on these specific aspects, we aim to develop more effective therapies for combating cancer.
Having studied that tumour cells flourish by SEs at critical oncogenes to improve signalling pathways, oncogenes are a class of genes that are mutated, which contributes to cancer development. This research speaks of how SEs also govern the expression and functionality of the protein synthesis machinery at the heart of oncogenic processes. Therapies designed to disrupt SEs, such as bromodomain and extra-terminal (BET) motif inhibitors, have shown promise as investigational drugs. Even so, their limited clinical effectiveness and potential for severe toxicity have hindered regulatory approval.
However, through a detailed study of a certain SE-regulated cascade, the researchers discovered Prmt1 as a potential downstream druggable target. This opens up the possibility of blocking SE-driven cancer while avoiding the effectiveness and toxicity problems associated with targeting Myc and KRAS. Discovering the network of RNA-binding proteins that regulate protein production, which fuels tumour growth, offers a hopeful connection between controlling genes in the cell’s nucleus and the process of making proteins in the cytoplasm. This connection could be a valuable target for developing therapies to combat cancer.
In conclusion, the work highlights potential druggable molecular mechanisms, mediated by the super-enhancer (SE) level, through which tumour cells promote translation to maintain carcinogenesis. The Hnrnpf-Prmt1-Ubap2l pathway is regulated by Myc, suggesting an alternative therapeutic approach to combat pancreatic cancer and perhaps other cancer types.
Edited by Colette Bilynsky
Reference:
- Antal, C.E., Oh, T.G., Aigner, S. et al. A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer. Nat Commun 14, 5195 (2023). https://doi.org/10.1038/s41467-023-40798-6
- Image created using https://www.biorender.com/
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