11:43am Saturday 07 December 2019

HDAC7 Gene Plays a Critical Role in Breast Cancer Stem Cells

In a study recently published in the journal Oncogene, a research team led by Tan Ince, M.D., Ph.D., described the mechanisms that help the gene histone deacetylase (HDAC) 7 control other genes, driving breast cancer and helping maintain cancer stem cells. In addition, the paper showed HDAC7 activity is downstream from other HDAC molecules, particularly HDAC1, possibly making it a better therapeutic target for future HDAC inhibitors.

“A lot of the HDAC inhibitors are inhibiting HDAC1,” said Dr. Ince, professor of pathology at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “However, we suspect that the end result may be through HDAC7. An HDAC7 inhibitor could be more specific for cancer stem cells than pan-HDAC inhibitor drugs.”

HDAC enzymes remove acetyl groups from DNA packaging proteins called histones, profoundly affecting gene expression – often for multiple genes. HDAC7 plays a unique, and sometimes contradictory, role. For example, inhibiting the enzyme increases acetylation globally for the histone H3k27ac but decreases it selectively at super-enhancers specifically in breast cancer stem cells.

As a result, inhibiting HDAC7 could eliminate rare reservoirs of these slow-growing, treatment-resistant cancer stem cells. Beyond that, HDAC7 inhibition could offer even more powerful therapeutic benefits.

“Inhibiting HDAC7 will inhibit several dozen oncogenes in cancer stem cells, such as c-MYC, CD44, CDKN1B and SLUG,” said Dr. Ince. “It provides a multiplier effect.”

HDAC7 can modulate these many oncogenes because it regulates gene promoters called super enhancers. Unlike most promoter regions, super enhancers can modulate gene expression even if they are not adjacent to the gene they control. In addition, they can affect multiple genes.

The study found that HDAC7 reduces the transcription of oncogenes associated with super enhancers. Modulating multiple oncogenes by inhibiting one target could be a game changer for cancer therapies. Down-regulating single oncogenes can be effective, but cancers often evolve escape mechanisms, allowing them to thrive without the inhibited gene. Being able to control a master switch, like HDAC7, could take away this advantage.

While the Ince lab will continue to investigate the mechanisms behind HDAC7 and other HDACs, they hope these results will encourage pharmaceutical companies to pursue HDAC7 inhibitors, opening up new therapeutic options for cancer patients.

“All our results point toward the needs to develop a very specific HDAC7 inhibitor,” said Dr. Ince. “Unfortunately, that agent doesn’t exist right now.”

 

Miller School of Medicine

 


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