OCRA grantee Dr. Sumegha Mitra of Indiana University and colleagues have identified the mechanism by which a specific deubiquitinating enzyme known as UCHL1 promotes the growth of high-grade serous ovarian cancer in some patients. This discovery may aid in the development of future ovarian cancer therapies, as it points to the potential effectiveness of a targeted inhibitor in treating certain tumors.
High-grade serous ovarian cancer, often referred to as HGSOC, is the most common type of ovarian cancer. Approximately 75% of epithelial ovarian cancers are classified as HGSOC. As such, when the term ‘ovarian cancer’ is used, it is typically in reference to HGSOC, unless another type is specified.
In their study, published in the AACR journal Molecular Cancer Research, Dr. Mitra and her colleagues observed elevated levels of the UCHL1 deubiquitinating enzyme in HGSOC tumors as compared with healthy tissue. They also found high concentrations of this deubiquitinating enzyme in fallopian tube lesions that are precursors to high grade serous ovarian cancer. These elevated UCHL1 levels corresponded to higher tumor grades and lower survival rates.
UCHL1, which stands for ubiquitin carboxyl-terminal hydrolase L1, is a deubiquitinating enzyme that is thought to be instrumental in breaking down damaged proteins in cells in a process referred to as protein degradation. This action is crucial to cell function because if damaged proteins are not cleared away, they will accumulate, which can lead to the death of the cell. This process of protein degradation is one of various functions necessary for maintaining protein homeostasis or the correct balance of proteins in a cell.
In their study, the researchers found that these elevated levels of UCHL1 in HGSOC tumors play a critical role in the regulation of protein homeostasis in the ovarian cancer cells. Ovarian cancer cells divide rapidly and are known to acquire chromosomal and genetic abnormalities, leading to a higher burden of damaged proteins than what is typically found in healthy cells. Dr. Mitra and her team discovered that the elevated levels of UCHL1 in these cancer cells seem to cause an increased expression of two different genes—acylaminoacyl peptide hydrolase (APEH) and proteasome subunit alpha 7 (PSMA7)—resulting in an uptick in the protein degradation necessary to maintain protein homeostasis and avoid cell death.
With this discovery of the role that UCHL1 plays in the progression of HGSOC and the mechanisms by which it seems to mediate protein homeostasis in cancer cells, Dr. Mitra and her colleagues have identified potential targets for future ovarian cancer treatments. “Our study identified the role of UCHL1 in mediating protein homeostasis in HGSOC and the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors,” the researchers wrote.
Read more at Molecular Cancer Research.
OCRA grantees are working hard to solve the mysteries of high-grade serous ovarian carcinoma, the most common type of ovarian cancer. See more HGSOC projects being supported by OCRA.