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Wistar Science Highlights: Advancement of a Novel Cancer Therapy and New Function of an Ovarian Cancer Gene

May 22, 2019

Wistar scientists advanced a novel anticancer treatment that targets the endoplasmic reticulum (a word you last heard in middle school cell biology) and discovered a new function for the ARID1 protein that is frequently mutated in ovarian cancer.

The endoplasmic reticulum (ER) is a cellular structure that oversees protein folding and assembly, and it activates stress response mechanisms in response to the accumulation of misfolded proteins or other stressful conditions.

In a study published online in the Journal of Medicinal Chemistry, the lab of Chih-Chi Andrew Hu, Ph.D., associate professor in Wistar’s Immunology, Microenvironment and Metastasis Program, and collaborators from the University of South Florida advanced a novel compound that specifically targets the ER stress response that is frequently hyperactivated in cancer.

“Certain cancers rely on the protective role of the ER stress response to sustain their growth in stressful environmental conditions,” said Hu.

The Hu lab has been developing compounds to block vital functions of the ER stress response as an effective way to attack various tumors.

In this study, Hu and collaborators created a molecule that is pharmacologically inactive and requires UV irradiation to be “turned on” into a very potent inhibitor.
This strategy brings a double benefit: it finely controls the inhibitor activity at a precise time and location by UV irradiation and it provides a real-time therapy readout, since the activated molecule emits fluorescence that can be tracked in cells and potentially in vivo.

ARID1 is a tumor suppressor gene, which means it keeps cell proliferation at bay and prevents tumor formation. Mutations in this gene translate into a loss or reduction in its function and, in combination with other genetic changes, can lead to cancer.

New research by the lab of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center and co-program leader of the Gene Expression & Regulation Program, sheds light on the function of the ARID1A protein, among the most frequently mutated gene across human cancers, including ovarian cancer.

Published online in Science Advances, the study showed that ARID1A plays a role in the spatial organization of the genome, which dictates how several feet worth of DNA molecules are packed in a microscopic space while also allowing each gene to be accessible for transcription — how DNA is copied into a new molecule of messenger RNA — at the appropriate time.

“This is a finely regulated process and we revealed that ARID1A has a critical role in it,” said Zhang.

Results showed that ARID1A dictates the genome-wide positioning of condensin II, which regulates gene expression through organizing chromosome structure. Therefore, when ARID1A function is lost as a consequence of gene mutation, condensin II distribution is altered and so is expression of a large set of genes. Therefore, ARID1A loss has broad effects on global gene expression.