New insights into protein reveal potential therapy for breast cancer

November 29, 2017 by Anna Williams, Northwestern University
cancer
Killer T cells surround a cancer cell. Credit: NIH

Northwestern Medicine scientists have discovered a new function for a protein called SET1B in the cytoplasm of cells, and demonstrated that targeting its role in regulating cellular metabolism may be able to treat triple-negative breast cancer.

The findings were published in the journal Genes and Development.

"This is a major discovery," said principal investigator Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics.

Lu Wang, PhD, a postdoctoral fellow in Shilatifard's laboratory, was the first author of the study.

SET1B is one of the six members of COMPASS, a family of enzymes which was first characterized by Shilatifard close to 20 years ago. The complex is known to be critical to gene expression: COMPASS catalyzes a key molecular event called histone methylation, which influences whether genes are turned on or off.

Dysregulation and mutations in some COMPASS genes have since been implicated in many types of human diseases, including cancer. But the function of SET1B, and its relationship with cancer, had remained unclear.

In the current study, the scientists first discovered that the majority of SET1B resides in the cytoplasm of cells—a surprising finding, given that all other members of COMPASS are found mainly in the nucleus.

"SET1B is also essential to the viability of different cancer cells, especially human ," Wang explained. "When the gene is deleted in using the gene-editing tool CRISPR, the cells do not survive. Interestingly, normal epithelia cells are fine with the depletion of SET1B."

To further understand SET1B's link to cancer growth, the scientists demonstrated that loss of SET1B leads to increased expression of several genes that modulate fatty acid metabolism—indicating a novel function for SET1B in regulating metabolic processes.

The Shilatifard laboratory also explored how these findings might offer novel strategies for treating cancer.

"At first, we thought about how to target SET1B—but a crystal structure of this 300kd protein doesn't exist, so we can't design a small molecule targeting it," Wang explained. "So we looked at the major downstream genes to target instead."

ADIPOR1 is one of the the scientists discovered was regulated by SET1B. ADIPOR1 is the receptor for adiponectin, a hormone that is known to have anti-diabetic effects. A Japanese research group had already developed a small molecule agonist drug to activate that receptor, called AdipoRon. As reported in Nature in 2013, AdipoRon improved insulin resistance and extend the lifespan of obese diabetic mice.

Given their discovery about the close relationship between SET1B and ADIPOR1, the Northwestern scientists decided to investigate using AdipoRon to treat triple-negative breast cancer. Triple-negative breast cancer is a type of breast cancer that lacks the three receptors targeted in common therapies, and as such, can be difficult to treat.

The team discovered that AdipoRon was capable of killing triple-negative in vitro, and further demonstrated in a mouse model of the cancer that treatment with the drug significantly reduced tumor size and increased animal survival.

Wang noted that the current study is the first to demonstrate how this small molecule drug, which has been used for the treatment of diabetes, could be used to treat human cancer.

In future studies, Shilatifard and his team intend to further analyze clinical data that suggest a correlation between SET1B gene expression and breast cancer patient survival, as well as investigate the development of other compounds that might target SET1B for treatments.

Explore further: Discovering a protein's role in gene expression

More information: Lu Wang et al. A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism, Genes & Development (2017). DOI: 10.1101/gad.306092.117

Related Stories

Discovering a protein's role in gene expression

November 10, 2017
Northwestern Medicine scientists have discovered that a protein called BRWD2/PHIP binds to histone lysine 4 (H3K4) methylation—a key molecular event that influences gene expression—and demonstrated that it does so via ...

Researchers discover a new target for 'triple-negative' breast cancer

November 20, 2017
So-called "triple-negative" breast cancer is a particularly aggressive and difficult-to-treat form. It accounts for only about 10 percent of breast cancer cases, but is responsible for about 25 percent of breast cancer fatalities.

Researchers identify potential therapeutic target in aggressive breast cancer cells

November 15, 2017
An especially aggressive breast cancer cell can respond to hormone therapy if they express a specific protein known as estrogen receptor beta (ERβ), according to new research published on the cover of Oncotarget. The findings ...

Genetic targets to chemo-resistant breast cancer identified

October 3, 2017
Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Unexpected findings uncover new understanding of gene expression

October 2, 2017
Northwestern Medicine scientists have discovered that the catalytic activity of the fly enzyme Trr and mammalian MLL3/MLL4—members of the COMPASS family of proteins central to gene expression—is not required for proper ...

Recommended for you

From the ashes of a failed pain drug, a new therapeutic path emerges

November 16, 2018
In 2013, renowned Boston Children's Hospital pain researcher Clifford Woolf, MB, BCh, Ph.D., and chemist Kai Johnsson, Ph.D., his fellow co-founder at Quartet Medicine, believed they held the key to non-narcotic pain relief. ...

Repurposing FDA-approved drugs can help fight back breast cancer

November 16, 2018
Screening Food and Drug Administration (FDA)-approved compounds for their ability to stop cancer growth in the lab led to the finding that the drug flunarizine can slow down the growth of triple-negative breast cancer in ...

Traditional chemotherapy superior to new alternative for oropharyngeal cancers

November 16, 2018
A drug increasingly used in combination with radiotherapy to treat a type of cancer that forms in the tonsils or the base of the tongue is inferior to a previously favored option, according to a large, clinical trial led ...

New 'SLICE' tool can massively expand immune system's cancer-fighting repertoire

November 15, 2018
Immunotherapy can cure some cancers that until fairly recently were considered fatal. In addition to developing drugs that boost the immune system's cancer-fighting abilities, scientists are becoming expert at manipulating ...

Anti-malaria drugs have shown promise in treating cancer, and now researchers know why

November 15, 2018
Anti-malaria drugs known as chloroquines have been repurposed to treat cancer for decades, but until now no one knew exactly what the chloroquines were targeting when they attack a tumor. Now, researchers from the Abramson ...

Standard chemotherapy treatment for HPV-positive throat cancer remains the most effective, study finds

November 15, 2018
A new study funded by Cancer Research UK and led by the University of Birmingham has found that the standard chemotherapy used to treat a specific type of throat cancer remains the most effective.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.