Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It is one of the leading causes of cancer-related death worldwide, with over 700,000 new cases and an estimated 600,000 HCC-related deaths each year. HCC occurs most often in people with chronic liver diseases such as hepatitis B, which is one of the main causes of HCC (especially in Asia). While surgery, liver transplantation, or radiological intervention may be a viable option for early-stage disease, the prognosis for late-stage HCC remains poor, with most patients eventually dying within 20 months of onset. diagnostic.
A team of researchers from Singapore Institute of Cancer Sciences (CSI Singapore), led by Prof. Daniel Tenen and Assistant Prof. Yvonne Tay, has launched a new study that aims to address an unmet clinical need. The team identified new pathways responsible for HCC.
Their findings were published in the prestigious scientific journal, Scientists progress, on October 1, 2021.
What are pseudogenes?
The Singapore CSI team focused on ‘pseudogenes’, a section of chromosome that is an imperfect copy of a functional gene. A good metaphor for understanding the distinction between DNA, chromosomes and genes is to think of the genome as a library. Our entire genome consists of many shelves of books, all of which instruct our bodies to produce different proteins, enzymes, and other fundamental cellular materials. A gene is a single book that contains instructions for a specific product – like a single protein – while DNA sequences are the sentences of its pages. A chromosome is a shelf of books because it contains many genes, and all the shelves combine to create the entire library (i.e. the genome). Humans generally have 23 pairs of chromosomes in each cell.
Each time a cell is created, the entire library of genomic information must be copied into the new cell. During this process, copying errors may occur, such as mutations. Pseudogenes describe this class of genes: genomic sequences similar to other genes but defective. Continuing with the book metaphor, these are books that contain misprints or typos. Pseudogenes do not code for any protein, but they look like genes that do, and are therefore called non-coding RNA (ncRNA).
Pseudogenes were once considered non-functional evolutionary relics due to their lack of coding potential, but recently these lncRNAs have recently been linked to patient prognoses and cancer subtypes. Despite the potential clinical importance of pseudogenes, only a handful of over 12,000 pseudogenes in humans have been characterized in cancers to date. In this study, Asst Prof Tay and his team established a previously unrecognized role for pseudogenes.
The role of pseudogenes in cancer
The group focused on a known gene that causes cancer, also known as an ‘oncogene’. The SALL4 oncogene is known to cause HCC and it contains eight pseudogenes. Since many pseudogenes are actively copied or “transcribed” into new cells, they postulated that pseudogenes may be involved in DNA methylation – a process in which a chemical methyl group (CH3) is added to the strand of DNA itself. This can affect how genes are expressed – sometimes DNA methylation can repress gene expression, which is exactly what the Singapore CSI team found.
Assistant Professor Tay explained: “We found that as SALL4 methylation increased, its expression decreased, suggesting the therapeutic potential of using DNA methylation as a regulatory mechanism to suppress DNA methylation. expression of SALL4 in HCC. With this interesting finding, we decided to go further to investigate the correlation between methylation of a specific region in SALL4 and SALL4 expression.
The team used CRISPR technology, which allowed them to target and block gene-specific DNA methylation. They found that certain SALL4 pseudogenes cause hypomethylation (the absence of CH3 methyl groups) in the CpG region. This hypomethylation – in other words, the reduction of the methylation profile in the region – leads to increased expression of the SALL4 gene with associated increased cell growth. “Therefore, blocking the pathways leading to hypomethylation of the SALL4 locus could have valuable therapeutic effects in HCC patients with elevated levels of SALL4,” said first author Dr. Kwon Junsu, researcher at CSI Singapore.
Importance and next steps
This new knowledge on SALL4 reexpression in HCC potentially opens avenues for the development of new therapeutic approaches and may change the treatment paradigm for patients.
“In the future, we plan to monitor the activity of pseudogenes that increase the expression of genes known to cause cancer through demethylation (ie the reduction of methyl groups). Through this, we hope to predict the activation of these oncogenes as well as cancer progression,” said Professor Tenen.