Epigenetic Therapy Eyed as Treatment for Endometriosis

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Female problems. Adult woman is sitting on a sofa at home and touching her lower stomach while suffering from cramps.
[Source: Povozniuk/Getty Images]

An especially painful and invasive form of endometriosis could be treated epigenetically, report scientists based at Michigan State University (MSU). To demonstrate this possibility, the scientists pharmacologically inhibited P300, a protein implicated in the dysregulation of endometrial epithelial cells, which normally line the uterus.

In severe endometriosis, P300 enjoys relatively free access to super-enhancers, genetic elements that determine cell function. When exposed to P300, the super-enhancers—particularly those associated with SERPINE1 (PAI-1)—become hyperactivated, stimulating endometrial epithelial cells to proliferate, spread, and form deep implants outside the uterus, resulting in severe pelvic pain.

This chain of events occurs in the absence of the ARID1A protein, an absence due to a mutation in the ARID1A gene. Ordinarily, the ARID1A protein co-localizes with super-enhancers, limiting access by P300 and preventing hyperacetylation. To compensate for the absence of ARID1A, the MSU team opted for an expedient solution, the inhibition of P300.

Details of this work appeared November 10 in the journal Cell Reports, in a paper titled, “ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation.”

“To identify epigenetic dependencies driving invasion, we use an unbiased approach to map chromatin state transitions accompanying ARID1A loss in the endometrium,” the article’s authors wrote. “ARID1A loss leads to H3K27 hyperacetylation and increased chromatin accessibility and enhancer RNA transcription at super-enhancers, but not typical enhancers, indicating that ARID1A normally prevents super-enhancer hyperactivation.

“ARID1A co-localizes with P300 at super-enhancers, and genetic or pharmacological inhibition of P300 in ARID1A mutant endometrial epithelia suppresses invasion and induces anoikis through the rescue of super-enhancer hyperacetylation. Among hyperactivated super-enhancers, SERPINE1 (PAI-1) is identified as an essential target gene driving ARID1A mutant endometrial invasion.”

The study’s lead authors, Mike Wilson, Ph.D., and Jake Reske, noted that inhibiting P300 could lead to better treatments for women suffering from the severe form of endometriosis associated with mutant ARID1A. (Wilson is a postdoctoral fellow in the MSU College of Human Medicine, and Reske is a graduate student in the MSU Genetics and Genome Sciences Program.) “There haven’t been many successful nonhormonal therapies for this form of endometriosis,” Reske added.

In laboratory experiments, Wilson and Reske demonstrated that P300 inhibition in ARID1A mutant cells suppresses invasion and induces anoikis, a form of programmed cell death. P300 is a kind of epigenetic drug; that is, it controls how genes are expressed. P300, the MSU team suggests, could be far more effective than current treatments, including surgery, hormone therapy, and pain management.

Endometriosis, particularly the kind associated with the ARID1A mutation, can be debilitating for many women, often leading to infertility.

“It can seriously impact women’s quality of life and their ability to have a family and work,” said Ronald Chandler, Ph.D., an assistant professor of obstetrics, gynecology, and reproductive biology, who supervised the study. “It’s not easy to treat, and it can become resistant to hormone therapy. The most clinically impactful thing we found is that targeting super-enhancers might be a new treatment for this deeply invasive form of the disease.”

Chandler and colleagues are already planning follow-up studies to find other epigenetic drugs that could target P300. The epigenetic approach, Chandler stated, could be used to treat other forms of endometriosis.

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