Although it reads like European license plate number, a protein known as ZMYND8 has demonstrated its ability to block metastasis-linked genes in prostate cancer, according to a study at The University of Texas MD Anderson Cancer Center. The findings, resulting from cell line and mouse model studies, are published in the July 28 online issue of Molecular Cell.
"These findings are important as cancer metastasis is a complicated process and is both devastating and clinically challenging," said Min Gyu Lee, Ph.D., associate professor of Molecular and Cellular Oncology. "For metastasis, cancer cells acquire migratory and invasive abilities and so gaining new insight into how this occurs and how to stop metastasis is crucial. We believe this study opens a window into this process."
Lee's study centered on modification of proteins crucial to gene regulation, known as histones. Alterations in histone modifications, including acetylation and methylation, are frequently associated with cancer development. Lee's group looked at ZMYND8 as a histone "reader" that could possibly impact gene expression by recognizing these histone modifications known as histone "marks."
"It has been well documented that the effects of histone acetylation and methylation on gene expression can be mediated by specific binding proteins called 'readers,'" said Lee. "We identified ZMYND8 as a reader for histone marks called H3K4me1 and H3K14ac, both of which are tied to metastasis-linked genes."
The research group also noted that ZMYND8 cooperated with a type of histone mark "eraser" called JARID1D to suppress metastasis-linked genes.
"These findings are of special interest in light of our earlier study that JARID1D levels are lower in metastasized prostate tumors than in normal prostate and primary prostate tumors," said Lee. "This study revealed a previously unknown metastasis-suppressive mechanism in which ZMYND8 counteracts the expression of metastasis-linked genes by reading dual histone marks H3K4me1 and H3K14ac and cooperating with JARID1D."
MD Anderson members of the study team included Na Li, Ph.D., Tsai-Yu Chen, Shilpa Dhar, Ph.D. and Pu-Yeh Kan, Ph.D., all of Molecular and Cellular Oncology; and Hong Wen, Ph.D. and Xiaobing Shi, Ph.D., Epigenetics and Molecular Carcinogenesis.
Other participating institutions included Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing; The Methodist Hospital Research Institute, Houston; Weill Cornell Medical College, New York City; Children's Hospital, Fudan University, Shanghai; Bloomberg School of Public Health, The Johns Hopkins University, Baltimore; the University of Miami School of Medicine, Miami; Baylor College of Medicine, Houston; The University of Texas Graduate School of Biomedical Science, Houston; and West China Hospital, Sichuan University, Chengdu, China.
The study was funded by the National Institutes of Health (CA157919, GM095659, ES025761, HG007538, GM078455 and GM105754); the Cancer Prevention and Research Institute of Texas (RP110183, RP110471 and RP140323); the Ministry of Science and Technology of China (2016FA05000700); the Tsinghua University Initiative Scientific Research Program; The Robert A. Welch Foundation (G1719); the National Natural Science Foundation of China (31400633); and the China Postdoctoral Science Foundation (2014T70069).