BU researchers discover therapeutic target of melanoma

Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma. Credit: Wikipedia/CC BY-SA 3.0

Researchers have identified a biomarker and a possible new therapy for melanoma.

Microphthalmia-associated transcription factor (MITF) is a protein that plays a pivotal role in the maintenance of the melanocyte (cells that make melanin) lineage, differentiation of normal and malignant melanocytes and the survival of melanoma cells.

"We have now detected the first useful chemical inhibitor of MITF," said corresponding author Rhoda Alani, MD, the Herbert Mescon Chair of Dermatology at Boston University School of Medicine.

While genetic mutations in human melanomas have been explored extensively over the past decade, the role of epigenetic alterations in melanoma development and progression has been less clearly defined.

The researchers found that inhibition of the epigenetic p300 Histone Acetyltransferase (HAT) enzyme prevents growth of human melanoma cells and cells with increased expression of MITF are most sensitive to this inhibition.

"When human melanoma cell lines were evaluated for growth effects using the chemical inhibitor of p300 HAT, the cell lines that were most sensitive to drug treatment were those that expressed high levels of MITF suggesting that MITF expression levels can predict melanoma sensitivity to such therapies," explained Alani, who also is chief of dermatology at Boston Medical Center.

According to the researchers, this inhibitor may have broad implications for the treatment of pigmented lesions in the skin and could potentially be used topically to treat hyperpigmentation.

They hope this study will provide an incentive to pursue additional epigenetic approaches to cancers, both as direct agents targeting specific cancers as well as adjuvant therapies to improve responses to cancer immunotherapies.

These findings appear in the online journal Cancer Research.

Year in review: Epigenome makes its debut

EPIGENOME DEBUT  Chemical modifications to DNA and histones can influence how genes are turned on and off during development and in health and disease. In 2015, scientists cataloged where these marks and other

Chemical modifications bring DNA to life

BY 

TINA HESMAN SAEY

In a landmark event more than a decade ago, geneticists unveiled the human genetic instruction book. This year, the book was turned into a movie adaptation in 3-D: Researchers cataloged how chemical modifications fold, compress and unwind the static DNA over time and how those modifications control when genes are on or off. 

The crew of researchers involved in the Roadmap Epigenomics Project premiered their findings in more than 20 scientific papers published in February (SN: 3/21/15, p. 6).

It was a blockbuster effort that would never make it in Hollywood. For one thing, it largely ignores the stars of the genome, the genes, and instead focuses on a dizzying cast of background characters known as epigenetic marks. The researchers cataloged these marks — chemical modifications either of DNA itself or proteins called histones — in more than 100 types of human cells. The epic effort revealed that gene variants associated with Alzheimer’s disease are more active in immune cells in the brain than in nerve cells as researchers had assumed. Another plot twist: Tightly packed areas of the genome are more vulnerable to cancer-causing mutations.

Like a classic movie in which viewers notice something new with each showing, researchers using data from this project and other efforts to view the genome in 3-D have made startling discoveries (SN: 9/5/15, p. 18). For instance, researchers found that a gene called FTO, thought to be a major genetic contributor to obesity, isn’t involved in fat production. Instead, a genetic variant hiding in the gene’s vicinity actually determines what type of fat the body builds (SN: 9/19/15, p. 6). Disorganized DNA may be a cause of aging, researchers also discovered (see "Not all bodies act their age").

The epigenome movie is sure to spark a series of sequels, each one revealing deeper secrets about human biology and suggesting new ways to improve human health.

GAME OF TAGS By mapping epigenetic marks in 111 types of tissues and cells (some shown here), researchers gained new insights into how the body is built and maintained. Some of these details aren’t captured in studies of DNA alone.

ROADMAP EPIGENOMICS CONSORTIUM