Ovarian cancer is the leading cause of death among gynecological cancers. Despite an often robust response to initial therapy, nearly 3 in 4 patients relapse within several years. These relapses are characterized by multidrug resistance, highlighting the need for novel therapeutic strategies.
A study led by Dr. Resham Bhattacharya employed a systems biology approach to identify and prioritize novel targets for ovarian cancer therapy. High-grade serous ovarian tumors under-express miR-15a and miR-16, which are involved in post-transcriptional regulation. To construct a network of genes regulated by miR-15a and miR-16, 72 experimentally validated miR-15a and miR-16 target genes were identified from a curated public database, and this network was expanded through the addition of 20 genes that interact heavily with the miR-15a/miR-16 target genes. From this expanded network, the top candidate gene was the previously uncharacterized KRCC1. KRCC1 transcript levels were significantly increased in recurrent human ovarian serous cystadenocarcinomas compared to primary tumors, and in chemo-resistant ovarian cancer cell lines compared to chemo-sensitive ovarian cancer cell lines. Additionally, high expression of KRCC1 significantly correlated with reduced survival in ovarian cancer patients in a public dataset. KRCC1 was found to encode a nuclear protein that interacts with serine/threonine-protein phosphatase (PP1CC) and Class I histone deacetylases (HDACs) to regulate apoptosis and cellular plasticity. Silencing KRCC1 in a xenograft mouse model reduced orthotopic ovarian tumor growth significantly more than cisplatin. These results suggest that the KRCC1 pathway regulates fundamental cancer cell phenotypes that may be relevant in multiple cancers. This opens the door to improve ovarian cancer treatment by developing new drugs and repositioning existing treatments for use in ovarian cancer.
The OSCTR Biostatistics, Epidemiology, and Research Design Core contributed essential expertise and resources to develop and conduct the systems biology approach used in this study.
Reference: Dwivedi SKD, Shameer K, Dey A, Mustafi SB, Xiong X, Bhattacharya U, et al. KRCC1: A Potential Therapeutic Target in Ovarian Cancer. FASEB J. 2020 Feb;34(2):2287-2300.
-Summary by Matt Slieff