Changes to the structure of the protein histone H3.3 may play a key role in silencing genes that regulate cancer cell growth, according to a study led by researchers from the Icahn School of Medicine at Mount Sinai and published online this month in the journal Nature Communications. According to the authors, this is the first study to identify this protein as a key regulator in cellular senescence, a process in which cells stop multiplying.
Cellular senescence has garnered significant scientific interest of late because it may be one key to prevent the initiation of cancer. However, little is known about this process and how genes that enable cells to divide and multiply (the cell cycle) are turned off. A growing body of evidence suggests that the process of cellular senescence is driven by changes in the protein complexes called chromatin in the nuclei of cells.
Using models of senescence, researchers found that histone variant H3.3, a protein that works closely with chromatin to package and regulate genetic material within cells, and in particular its clipped form, help to silence target genes that regulate the cell cycle.
Could the presence of this protein stop cells from dividing? Indeed using genome-wide transcriptional profiling, the researchers revealed that expression of clipped H3.3 silences genes that regulate the division and duplication of a cell.
"Cellular senescence creates a chromatin environment that represses cell multiplication, and thus cell or tumor growth, but how this happens molecularly is what we sought to discover," said lead investigator Emily Bernstein, PhD, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. "What we found was that histone H3.3 and its clipped form, which lacks 21 amino acids of the histone tail and associated modifications, prevents normal cells from dividing. Clipped H3.3 may be a marker of cells that stop proliferating and has implications for cancer, in particular cancers like melanoma that have a senescence phase."
This research was supported by a grant from the National Cancer Institute, University of Cambridge, Cancer Research UK, Hutchinson Whampoa and the Human Frontier Science Program, funds from The Ellison Medical Foundation, and a Developmental Research Pilot Project Program at Mount Sinai.
About the Tisch Cancer Institute
The Tisch Cancer Institute (TCI) is a world-class translational cancer institute established in December 2007. TCI has recruited more than 30 acclaimed physicians and researchers specializing in basic research, clinical research, and population science; built outstanding programs in solid tumor oncology; enhanced existing robust programs in hematological malignancies; and advanced the study of cancer immunology and vaccine therapy. The completion of the Leon and Norma Hess Center for Science and Medicine in 2012 is enabling the recruitment of up to 20 additional cancer researchers on two full research floors, with 48,000 square feet of space dedicated to cancer research.
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The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community-based facilities to tertiary and quaternary care.
The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.
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