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Published on: November 2, 2014
KRCC1: A potential therapeutic target in ovarian cancer
Shailendra Kumar Dhar Dwivedi1, Khader Shameer2, Anindya Dey1
1Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Abstract:
Using a systems biology approach to prioritize potential points of intervention in ovarian cancer, we identified the lysine rich coiled-coil 1 (KRCC1), as a potential target. High-grade serous ovarian cancer patient tumors and cells express significantly higher levels of KRCC1 which correlates with poor overall survival and chemoresistance. We demonstrate that KRCC1 is predominantly present in the chromatin-bound nuclear fraction, interacts with HDAC1, HDAC2, and with the serine-threonine phosphatase PP1CC. Silencing KRCC1 inhibits cellular plasticity, invasive properties, and potentiates apoptosis resulting in reduced tumor growth. These phenotypes are associated with increased acetylation of histones and with increased phosphorylation of H2AX and CHK1, suggesting the modulation of transcription and DNA damage that may be mediated by the action of HDAC and PP1CC, respectively. Hence, we address an urgent need to develop new targets in cancer.
Insights
Lysine rich coiled-coil 1 (KRCC1) is a novel target in ovarian cancer, showing higher expression in tumors and correlating with poor survival. Silencing KRCC1 inhibits tumor growth and enhances chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- High-grade serous ovarian cancer (HGSOC) presents a significant clinical challenge with limited therapeutic options.
- Identifying novel molecular targets is crucial for improving patient outcomes and overcoming chemoresistance in HGSOC.
Purpose of the Study:
- To identify and characterize novel therapeutic targets in ovarian cancer using a systems biology approach.
- To investigate the role of lysine rich coiled-coil 1 (KRCC1) in HGSOC progression and chemoresistance.
Main Methods:
- Systems biology analysis to identify potential therapeutic targets.
- Expression analysis of KRCC1 in patient tumors and cell lines.
- Biochemical assays to determine KRCC1 localization and protein interactions (HDAC1, HDAC2, PP1CC).
- Functional studies involving KRCC1 silencing to assess effects on cellular plasticity, invasion, apoptosis, and tumor growth.
Main Results:
- KRCC1 is significantly overexpressed in HGSOC tumors and cells, correlating with poor overall survival and chemoresistance.
- KRCC1 localizes to the chromatin-bound nuclear fraction and interacts with HDAC1, HDAC2, and PP1CC.
- KRCC1 silencing inhibits cellular plasticity and invasion, potentiates apoptosis, and reduces tumor growth.
- KRCC1 inhibition leads to increased histone acetylation and H2AX/CHK1 phosphorylation, indicating modulation of transcription and DNA damage.
Conclusions:
- KRCC1 is a promising therapeutic target for ovarian cancer, impacting key cancer hallmarks.
- Targeting KRCC1 may offer a novel strategy to overcome chemoresistance and improve survival in HGSOC patients.
- The interaction of KRCC1 with HDACs and PP1CC suggests specific molecular mechanisms underlying its oncogenic function.
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