A novel gene was discovered recently that suppresses the growth of human tumors in a number of different cancers. The study, published in the journal Nature Medicine, found that the gene HACE1, an acronym for HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1, is able to help cells deal with various forms of stress that cause tumor formation [1].
What is a ubiquitin protein ligase?
Ubiquitin is a small protein consisting of only 76 amino acids. It is attached to other proteins by an enzyme called a protein ubiquitin ligase in a process known as ubiquitination. Ubiquitin acts as a marker that targets proteins for proteolysis (meaning cleavage of proteins by proteases, enzymes that degrade protein molecules). Ubiquitin is appropriately named since it is ubiquitious and present in essentially all cell types.
The process of ubiquitination occurs in three steps:
- Ubiquitin is activated by an E1 ubiquitin-activating enzyme.
- Activated ubiquitin is transferred from E1 to the ubiquitin-conjugating enzyme E2.
- The E3 ubiquitin-ligating enzyme interacts with both the E2 enzyme and the substrate (meaning the molecule upon which an enzyme acts), and transfers ubiquitin to the substrate protein.
- Frequently, the process is repeated to form a polyubiquitin chain.
The 2004 Nobel Prize in Chemistry was awarded to Aaron Ciechanover and Avram Hershko (Technion Israel Institute of Technology, Haifa, Israel), and Irwin Rose (University of California, Irvine, US) for the discovery of ubiuitin-mediated protein degredation.
Study results
The British Columbia Cancer Research Centre study, done in both mice and human tumor cells, demonstrated that HACE1 is a tumor suppressor. Researchers “knocked out” the gene in mice (meaning the gene was inactivated so that it wasn’t expressed) and found that as the mutant mice aged, they spontaneously developed a spectrum of tumors, including melanoma (the most serious form of skin cancer), hepatocellular carcinoma (primary liver cancer), spontaneous lung adenocarcinoma (lung cancer), angiosarcoma (tumors that develop from blood or lymphatic vessels), mammary carcinomas (breast cancer) and lymphomas (a family of cancers that develop from immune system cells called lymphocytes).
Additionally, loss of HACE1 expression also rendered the mice susceptible to environmental and genetic second hits for the development of multiple cancers. The mutant mice were subjected to various forms of stress, including ultraviolet radiation, lung carcinogens or other genetic alterations, and the result was a dramatic increase in cancer growth. The mice developed breast, lung, and liver cancers, as well as lymphomas, melanomas and sarcomas.
When HACE1 was expressed in human tumor cells, the cells lost their ability to form tumors. The tumor-suppressor function of HACE1 was shown to be dependent on its E3 ligase activity and the researchers suggest that HACE1 regulates cell cycle progression during cell stress by influencing degredation of the protein cyclin D1, which plays a key regulatory role during the G1 phase of the cell cycle.
What does all this mean? A distinctive feature of cancer is the subversion of normal growth signaling pathways and cell cycle regulators are natural targets during tumor development. Overexpression or amplification of cyclin D1, an oncogene, has been identified or associated with a range of human cancers, including B mantle cell lymphoma [2], non-small cell lung cancers [3], head and neck squamous cell carcinoma [4], pancreatic carcinomas [5], bladder cancer [6] and breast carcinoma [7]. If scientists can express HACE1 in human tumors or prevent HACE1 inactivation, it may be possible to improve cancer treatments.
References
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Zhang et al. The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nat Med. 2007 Oct;13(9):1060-1069. Epub 2007 Aug 12.
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Gansauge et al. Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res. 1997;57:1634-7.
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Barnes and Gillett. Cyclin D1 in breast cancer. Breast Cancer Res Treat. 1998;52(1-3):1-15.
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The cell cycle is a series of ordered events that occur in a cell between it’s initial formation and eventual duplication and division into two daughter cells. Cells in the human body normally reproduce up to ~50 times [1], doubling their number with each cell cycle. Stem cells provide a pool of dividing cells to replace those that have died.
Interphase, the period between cell divisions, is where most cells remain for at least 90% of the cell cycle. Interphase consists of three phases: G1 (for gap 1), S phase (for synthesis) and G2 (for gap 2). During G1, the cell undergoes rapid growth and metabolic activity, including production of RNA and synthesis of protein. For the cell to divide and produce an identical copy of itself, its genome must be duplicated. DNA replication occurs in S phase. During G2, cell growth continues and the cell prepares for division. Cell division or mitosis occurs in M phase.
In normal cells, during G1 there are specific genes that control the speed of the cell cycle. These genes, called tumor suppressors and oncogenes, are mutated (meaning damaged) in cancer cells and can result in uncontrolled reproduction. Additionally, unlike normal cells, cancer cells do not stop reproducing after ~50 divisions. Thus, a cancer is an uncontrolled proliferation of cells.
Tumor suppressors
Tumor suppressors are genes that either slow down cell division, DNA repair or cell death (a process known as apoptosis or programmed cell death). These processes are all interconnected. Throughout the cell cycle there are DNA damage checkpoints; if there is damage, DNA replication is paused while the damage is repaired. In the event that the damage cannot be repaired, the cell initiates apoptosis. When a tumor suppressor gene is mutated (increasing either their expression or function) and inactivated (meaning turned off; also referred to as “loss of function”), cells can grow out of control and lead to cancer. As of 2003, 174 tumor suppressor genes were identified [2], including:
The analogy is often made between tumor suppressors and the brakes on a car. Just as the brakes keep a car from going too fast, tumor suppressors keep the cell from dividing too quickly.
Oncogenes
In contrast to tumor suppressors that are inactivated, oncogenes are permanently activated. Oncogenes are mutated forms of genes called proto-oncogenes that normally control cell division and the degree of differentiation (a process by which cells acquire “a type”). When a proto-oncogene is permanently activated (meaning turned on; also referred to as “gain of function”) through mutation, it is called an oncogene. When this occurs, cell division happens too quickly and cells can grow out of control and lead to cancer.
Some classic examples of proto-oncogenes are:
- Neuroblastoma RAS viral oncogene homolog (NRAS)
- v-Myc myelocytomatosis viral oncogene homolog (MYC)
- Epidermal growth factor receptor (EGFR)
Oncogenes are analogous to the accelerator on a car. Oncogenes “drive” the cell cycle, speeding up cell growth and division.
Two-hit hypothesis
In 1971, Alfred Knudson proposed the two-hit hypothesis for tumorigenesis [3]. While studying children with retinoblastoma (a cancer of the eye), Knudson noted differences between patients with inherited tumors and patients that appeared to have no susceptibility to the disease. Statistical analysis revealed that the fraction of cases not yet diagnosed in patients with the hereditary form of the disease decreased exponentially with age, suggesting that one mutational event caused the cancer.
His findings demonstrated that multiple mutational events or “hits” were necessary to cause cancer. Everyone has two copies of most genes, one from their mother and one from their father. Normally, one mutation is not enough for cancer to develop, unless you were born with it. This occurs with people who have familial cancer (meaning occurs in families). People who were born with a mutation in a tumor suppressor are predisposed to cancer and only need damage in the other copy for cancer to develop. Those born without the mutation require two mutational events to occur, statistically much less likely. However, there are cases where a single mutation is sufficient to cause an effect, notably the p53 gene.
The current view of cancer has built upon the two-hit hypothesis. Today, cancer is modeled as an accumulation of mutations in both tumor suppressors and oncogenes. Additionally, epigenetic changes (meaning something that affects a cell without changing its DNA sequence) [4] and microRNAs [5] play a role. Thus, a number of genetic and epigenetic alterations are thought to be required for tumor progression and the development of cancer.
The scope of this article is limited to a basic overview of the two general classes of genes that contribute to cancer. For a more information, Nature Milestones in Cancer highlights achievements made in cancer research since the end of the nineteenth century and provides historical perspective on how given concepts evolved.
References
- L Hayflick. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965 Mar;37:614-36.
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- Yang and Fu. TSGDB: a database system for tumor suppressor genes. Bioinformatics. 2003 Nov 22;19(17):2311-2.
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- AG Knudson. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3.
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- AP Feinberg. The epigenetics of cancer etiology. Semin Cancer Biol. 2004 Dec;14(6):427-32.
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- Calin and Croce. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006 Nov;6(11):857-66.
View abstract
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