COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer
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Shujun Gao1,2,*, Lekun Fang2,3,*, Liem Minh Phan2, Aiham Qdaisat2, Sai-Ching J. Yeung4,5, Mong-Hong Lee2,3,6,7
1Obstetrics and Gynecology Hospital Fudan University, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
2Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
3Department of Colorectal Surgery, Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
4Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
5Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
6Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
7Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
*These authors have contributed equally to this work
Lekun Fang, e-mail: email@example.com
Mong-Hong Lee, e-mail: firstname.lastname@example.org
Keywords: CSN6, E6AP, p53, cervical cancer, ubiquitination
Received: February 04, 2015 Accepted: July 23, 2015 Published: August 03, 2015
Cervical cancer is one of the leading causes of cancer death in women. Human papillomaviruses (HPVs) are the major cause in almost 99.7% of cervical cancer. E6 oncoprotein of HPV and E6-associated protein (E6AP) are critical in causing p53 degradation and malignancy. Understanding the E6AP regulation is critical to develop treating strategy for cervical cancer patients. The COP9 signalosome subunit 6 (CSN6) is involved in ubiquitin-mediated protein degradation. We found that both CSN6 and E6AP are overexpressed in cervical cancer. We characterized that CSN6 associated with E6AP and stabilized E6AP expression by reducing E6AP poly-ubiquitination, thereby regulating p53 activity in cell proliferation and apoptosis. Mechanistic studies revealed that CSN6-E6AP axis can be regulated by EGF/Akt signaling. Furthermore, inhibition of CSN6-E6AP axis hinders cervical cancer growth in mice. Taken together, our results indicate that CSN6 is a positive regulator of E6AP and is important for cervical cancer development.
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