Controlling Survivin Activity Could Stop Breast Cancer Without Harming Normal Tissue

Despite evidence linking high levels of the protein survivin to breast cancer, the mechanism that determines whether survivin acts to promote or inhibit cancer development has only now been explained.

Survivin is a member of the inhibitor of apoptosis (IAP) family. This protein inhibits caspase activation, thereby interfering with apoptosis. This has been shown by disruption of survivin induction pathways, which leads to increase in apoptosis and decrease in tumor growth. Survivin localizes to the mitotic spindle by interaction with tubulin during mitosis and may play a contributing role in regulating mitosis. The survivin protein is expressed highly in most human tumors and fetal tissue, but is completely absent in mature normal cells. This fact makes survivin an ideal target for cancer therapy, as cancer cells are targeted while normal cells are left alone. The molecular mechanisms of survivin regulation are still not well understood, but regulation of survivin seems to be linked to the p53 protein. It also is a direct target gene of the Wnt pathway and is upregulated by beta-catenin.

Investigators at Brown University (Providence, RI, USA) had previously shown that survivin had a dual function that was dependent on its subcellular localization. In the cytosol, survivin blocked apoptosis by inactivating caspase proteins. However, in the nucleus it facilitated cell division by regulating chromosomal movement and cytokinesis. Survivin was acetylated by CREB-binding protein (CBP), which restricted its localization to the nuclear compartment and thereby inhibited its antiapoptotic function.

In a study published in the February 9, 2012, online edition of the Journal of Biological Chemistry the investigators extended our understanding of how survivin works by showing that histone deacetylase 6 (HDAC6) was responsible for abrogating CBP-mediated survivin acetylation in an estrogen-receptor (ER) positive breast cancer cell line. Deacetylized survivin could then escape to the cytosol and prevent apoptosis, thereby stimulating tumor development.

HDACs are a group of enzymes closely related to sirtuins. They catalyze the removal of acetyl groups from lysine residues in histones and nonhistone proteins, resulting in transcriptional repression. HDACs have a role in cell growth arrest, differentiation, and death and this has led to substantial interest in HDAC inhibitors as possible antineoplastic agents. In the current study the investigators found that HDAC6 directly bound to survivin, an interaction that was enhanced by CBP. In quiescent breast cancer cells in culture and in malignant tissue sections from ER+ breast tumors, HDAC6 localized to a perinuclear region of the cell, undergoing transport to the nucleus following CBP activation where it then deacetylated survivin.

“It is not just how much HDAC6 is present – what is important is where it is,” said senior author Dr. Rachel Altura, associate professor of pediatrics at Brown University. “We need to look not only at the levels, but also where it is in the cell. You always have to worry about all the things you do not know that you are targeting. “If we can target HDAC6, we can maybe block survivin from coming out of the nucleus and maintain it in its good state.”

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