Nav: Home

Cellular senescence prevented by the SETD8 enzyme

March 08, 2017

An enzyme that blocks cellular senescence and its mechanisms has been discovered by a research team from Kumamoto University, Japan. They found that a reduction of the enzyme SETD8, which regulates cell proliferation and gene function, results in the promotion of cell aging features.

Many types of cells in the body eventually stop proliferation as their ability to divide decreases. This is called cellular senescence and is considered to be an important factor related to the aging process and life span. Although there are various etiologies of cellular senescence, the mechanism is still not well understood. In particular, stress-induced cellular senescence occurs when genomic DNA is damaged by physical factors, such as radiation, or by DNA-targeting chemicals. Additionally, when cells start becoming cancerous, cellular senescence occurs to prevent the onset of cancer. Unfortunately, increased age makes it easier to become sick, so it is important to properly control this particular cell function.

Senescent cells have a hypertrophied and flattened morphology, and lose their proliferative capacity. In recent years, it has been discovered that senescent cells secrete a variety of proteins which sometimes promote chronic inflammation as well as cancer development by acting on the surrounding cells. Since senescent cells are more active than expected, cellular senescence is considered to be the cause of the aging phenomena for the whole body. For example, it has been reported that when senescent cells of old mice are eliminated, whole body aging can be suppressed. In other words, if we can adjust cellular senescence, whole body aging may be controlled.

The team from Kumamoto University has been researching the mechanisms of cellular senescence from the viewpoint of epigenetics, a research field that studies the changes in gene expression by molecular modifications. They screened for factors related to the senescence of cultured human fibroblasts (cells in connective tissue which aid in cell proliferation, differentiation, and repair) by using various cell- and gene-mediated analyses. They discovered that the enzyme SETD8 methyltransferase, which adds methylation on histone H4 lysine 20 (H4K20), regulates senescent features.

Normal cells stop proliferation after dividing many times (replicative senescence), and when oncogenes are activated for cancer initiation, senescence occurs to prevent it (oncogene induced senescence). In the past, SETD8 was reported to regulate cell proliferation and gene function via H4K20 mono-methylation, but its relation to cellular senescence was unknown. The researchers, however, found that SETD8 decreased markedly in senescent cells. When they performed a gene knockdown experiment (using RNA interference) to suppress the function of SETD8 in fibroblasts, cellular senescence was induced with typical features. Furthermore, using a drug that inhibits the enzyme activity of SETD8, similar senescent cells appeared. In other words, SETD8 plays a role in preventing cellular senescence.

The researchers then comprehensively analyzed all gene expression in senescent cells with decreased SETD8. The results showed that the expression of genes involved in cellular senescence had increased, particularly the genes for ribosomal proteins and ribosomal RNAs responsible for cellular protein synthesis, and the genes of proteins that inhibit cell proliferation. This shows that a loss of SETD8 augments protein synthesis and growth arrest in senescent cells via gene regulation.

Senescent cells need large amounts of energy to maintain cellular functions such as protein synthesis and secretion. The researchers previously reported that energy production in mitochondria is markedly increased in senescent cells (Takebayashi et al. Aging Cell, 2015). Now, researchers have found that the activation of mitochondria is regulated by SETD8, and microscopic observations confirmed that the nucleolus and mitochondria were remarkably developed in SETD8 depleted cells. Therefore, cell senescence and its corresponding metabolic activities are promoted by a decrease in SETD8.

This research reveals that SETD8 protects against cellular senescence. It is expected that this result will be useful for understanding the mechanisms of senescence and developing a way to control cell aging.

This finding was first reported in Cell Reports on February 28th, 2017.

H. Tanaka, S.-i. Takebayashi, A. Sakamoto, T. Igata, Y. Nakatsu, N. Saitoh, S. Hino, and M. Nakao, "The setd8/pr-set7 methyltransferase functions as a barrier to prevent senescence-associated metabolic remodeling," Cell Reports, vol. 18, pp. 2148-2161, Feb. 2017. DOI: 10.1016/j.celrep.2017.02.021

Kumamoto University

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Moving Forward
When the life you've built slips out of your grasp, you're often told it's best to move on. But is that true? Instead of forgetting the past, TED speakers describe how we can move forward with it. Guests include writers Nora McInerny and Suleika Jaouad, and human rights advocate Lindy Lou Isonhood.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...