With the advent of epigenetics, researchers have focused their research efforts on an “on and off” switch phenomena that is thought to be the mechanism behind the development of different types of cancer. Epigenetics is the change in gene expression controlled by environmental factors.
The current research hypothesis is that cancer develops from environmental and genetic changes to pre-cancer cells. However, cancer progression itself causes the activation of other cancer associated genes through an epigenetic switch supported by the fact that tumors develop through different stages.
When cells rapidly grow during cancer progression, they remain at their current stage of development and their cell characteristics do not change. This is the reason that there are so many types of leukemia the characteristics that a leukemia cell possesses when it begins to rapidly grow and expand are the characteristics that it will keep until the rapid growth stops. During cancer progression, there are different stages of rapid growth and differentiation of cells. The control that allows for this switch between growth and differentiation can only be achieved through reversible mechanisms, such as epigenetic changes.
The Sarkar research team have proposed that epigenetic changes are fully involved in cancer from pre cancer cell formation to the different types of cancer progression, with epigenetics the key to control the growth and different types of tumors.” While the specific details of the epigenetic code that regulates these changes has not been discovered, the fact that we have a possible explanation for the reversible and ever-changing characteristics for cancer progenitor cells is very exciting,” said Sibaji Sarkar, PhD, instructor of medicine at BUSM and the articles corresponding author.
“If we believe that all of the irreversible changes, mutations and effects of carcinogens make cells rapidly grow, then the mechanism that allows cells to stop growing and assume new changes in character must be of great importance,” said Sarkar.”The study of cancer progression is key to understanding how cancer cells continue to differentiate.”
A previous study has demonstrated that long non-coding RNA are involved in activating cancer genes. A new study by the Salk Institute for Biological Studies identified that long non-coding RNAs act as an on/off switch for the COX-2 gene which is tied to inflammation and Cancer.
The Cox-2 gene is responsible for the inflammation response which acts against pathogens and damaged cells. However, the inflammation response can contribute to the growth and spread of tumors at the early stages of cancer.
“Deciphering the mechanism of COX-2 gene regulation is of great clinical interest,” says senior author Beverly Emerson, a professor in Salk’s Regulatory Biology Laboratory and holder of the Edwin K. Hunter Chair. “COX-2 is instrumental in the development of several types of cancer, including colon, breast and prostate cancer. Strategies that specifically modulate COX-2 activity could be an attractive treatment approach.”
Human mammary epithelial cells were used and it was discovered that a long non coding RNA strand called PACER (p50-associated COX-2 extragenic RNA) combines with molecules that change the activity of the COX-2 gene. PACER acts by removing a molecule called p50 from the COX-2 gene, causing COX-2 to go into overdrive. This is the first time scientists have shown that non-coding RNAs must be activated in order to stop the activity of p50, a gene repressor. Blocking p50 promotes the assembly of molecular activators of gene expression, which gears up COX-2 activity.
Early in the disease process, instead of activating the immune system to clear malignant cells from the body, COX-2 aids the growth and spread of tumors. In later stages of disease, cancer cells often shut off COX-2 activity, as if at that stage COX-2 is no longer beneficial for tumor growth because it exposes spreading tumor cells to the immune system. That presents the opportunity to trigger COX-2 expression via PACER in late-stage cancers to aid immune system clearance of metastatic cells.
“This could be a potential treatment for late-stage cancers,” said Krawczyk. “We could possibly use small molecules to reactivate COX-2 activity, or perhaps even supply PACER itself, to fight the disease.”
Shannon Byler, Sibaji Sarkar. Do epigenetic drug treatments hold the key to killing cancer progenitor cells? Epigenomics, 2014; 6 (2): 161 DOI: 10.2217/epi.14.4
Shannon Byler, Sarah Goldgar, Sarah Heerboth, Meghan Leary, Genevieve Housman, Kimberly Moulton And Sibaji Sarkar. Genetic and Epigenetic Aspects of Breast Cancer Progression and Therapy. Anticancer Research, May 2014
M. Krawczyk, B. M. Emerson. p50-Associated COX2 Extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF- B complexes. eLife, 2014; DOI: 10.7554/eLife.01776