The tumor-suppressing protein ZMYND11 may help predict survival in patients with triple-negative breast cancer and possibly other tumors. A study led by Xiaobing Shi, Ph.D., an assistant professor in the Department of Biochemistry and Molecular Biology at The University of Texas MD Anderson Cancer Center, identified ZMYND11 as a histone reader protein that specifically recognizes methylated histones and prevents uncontrolled transcription. To do this, Dr. Shi and his colleagues performed a detailed structural analysis, cell line and mouse experiments, and analyses of human tumor specimens.
During normal gene expression, transcription of an expressed gene is performed by RNA polymerase II. As RNA polymerase II travels along the DNA, a group of proteins associated with the polymerase leaves behind histone markers that serve as “placeholders” to indicate which regions of the gene have been transcribed. These markers serve several purposes, many of which have yet to be fully characterized in humans.
Methylation is one of the most common histone markers and can serve a wide variety of purposes. Dr. Shi’s group found that ZMYND11 binds to a specific type of methylated histone (H3.3) and then prevents a critical step in transcription.
By preventing the transcription of genes marked with methylated H3.3, ZMYND11 is able to repress the aberrant expression of oncogenes in preclinical malignancies. ZMYND11 may also help activate genes that encode other tumor-suppressing proteins, but that function is less clear.
To understand how ZMYND11 affects cancer cell growth, the researchers expressed ZMYND11 in a triple-negative breast cancer cell line. Expression of normal ZMYND11 suppressed tumor cell growth, but when Dr. Shi’s group modified ZMYND11 to prevent it from binding to methylated H3.3, it was unable to suppress growth. Similarly, mice injected with tumor cells expressing normal ZMYND11 had much smaller tumors than those injected with cells expressing non-functional ZMYND11.
Because they found such striking results in mice, Dr. Shi’s group decided to survey ZMYND11 expression levels in triple-negative breast cancer specimens. The researchers analyzed tumor samples from 120 patients with triple-negative breast cancer and found that women whose tumors expressed high levels of ZMYND11 had an 80% 10-year disease-free survival rate, whereas those women whose tumors expressed low levels of ZMYND11 had a 50% disease-free survival rate.
These findings, which were published in Nature in April, indicate that ZMYND11 may be an important prognostic marker for patients with triple-negative breast cancer and possibly other cancers.
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OncoLog, June 2014, Volume 59, Issue 6