Differential Impact of the Ubiquitin-Proteasome System on Clear Cell Carcinoma and High-Grade Serous Ovarian Cancer

Review Article

Austin Biochem. 2018; 3(1): 1015.

Differential Impact of the Ubiquitin-Proteasome System on Clear Cell Carcinoma and High-Grade Serous Ovarian Cancer

Werts S and Ye J*

¹Department of Biochemistry, Salem College, USA

*Corresponding author: Ye J, Department of Biochemistry, Salem College, 601 S Church St, Winston- Salem, NC, 27101, USA

Received: April 04, 2018; Accepted: April 23, 2018; Published: April 30, 2018


Ovarian cancer is particularly deadly and difficult to target because of its aggressive nature. With high mortality rates, current studies are focused on improving early detection and prevention methods as well as developing new treatments. To successfully develop these therapeutic options, researchers first need to understand how the cancer forms, spreads, and functions. Since ovarian cancer is composed of many heterogeneous subtypes, such as high-grade serous ovarian cancer and clear cell epithelial ovarian cancer, the nuances of each type need also be examined and understood in order to target each individually. It has been determined that each subtype has a unique relationship with the tumor suppressor, p53. Understanding how each subtype interacts with p53 can lead to specialized treatment mechanisms that target these interactions. MDM2 and ADRM1, over expressed in clear cell carcinoma and high grade serous ovarian cancer respectfully, are key components of these interactions within ovarian cancer. MDM2 is a negative regulator of p53, while ADRM1 aids in protein degradation. The overexpression of each molecule acts specifically to aid ovarian cancer in survival. In this review, recent advances in studying ovarian cancer subtypes will be covered, as well as how these subtypes relate to the ubiquitin-proteasome system and the key tumor suppressor in human cells, p53.

Keywords: Ubiquitin-proteasome system; p53; Clear cell carcinoma; Highgrade serous ovarian cancer


DUBs: Deubiquitinating Enzymes; HGSC: High-Grade Serous Ovarian Cancer; CCC: Clear Cell Carcinoma; MDM2: Murine Double Minute 2; UPS: Ubiquitin-Proteasome System; ROCA: Risk Of Ovarian Cancer Algorithm; CIC: Cancer Initiating Cell; BRCA: Breast Cancer Gene; ADRM1: Adhesion Regulating Molecule 1; CA- 125: Serum Cancer Antigen-125


Ovarian cancer, one of the deadliest and most aggressive gynecological malignancies, is the fifth most common cause of cancer death in women [1,2]. As recently as 2017, the annual ovarian cancer mortality was approximately 65% of the incidence rate due to low predictive value in screening procedures for women without increased risk factors [3]. As a result, only 15% of patients are diagnosed with localized disease and many patients are diagnosed in stage III or IV [1]. The four main histological subtypes within epithelial ovarian cancer are serous, clear cell, endometrioid, and mucinous adenocarcinomas [2,4,5]. Each subtype has its own unique abnormalities, making diagnosis and treatment of ovarian cancer difficult. While all women are susceptible to ovarian cancer, increased risk factors include familial history, nulliparity, lack of breast feeding, and infertility [1]. About 20% of ovarian cancers are familial, linked mostly to Breast Cancer Alleles 1 and 2, (BRCA1 or BRCA2), though other gene mutations have been implicated as well [3]. BRCA1 and BRCA2 produce tumor suppressor proteins and mutations in these genes and are commonly found in breast cancer as well as ovarian cancer. The overall five-year survival rate for ovarian cancer patients has improved over the last decade due to improvements in general cancer treatment methods, but survival for advanced stages is still less than 40%. Research in ovarian cancer is currently focused on defining the mechanism of formation and spread of each subtype, improving early detection and prevention, and creating new therapeutic options [1]. The goal of this review is to highlight current research on serous and clear cell epithelial ovarian cancer and determine if the ubiquitinproteasome system can be targeted in each cancer to create new screening tests or treatment options.

One of the most important proteins in regard to tumor suppression in humans is p53. Wild-type p53, a component of the ubiquitin-proteasome system, is activated by cellular stress and inhibits cell cycle progression, prompts apoptosis, or stimulates senescence [6]. In many human cancers, p53 is inactivated, either through mutation or other mechanism [7]. This allows tumor growth to continue unchecked. In some ovarian cancer subtypes, such as high-grade serous ovarian cancer, the p53 protein is mutated or deleted, and in some, such as clear cell carcinoma, the wild-type p53 protein is inactivated due to interaction with other molecules [8,9]. Inactivation of p53 can occur through interactions with various molecules within the ubiquitin-proteasome system, most commonly MDM2 and other Deubiquitinating Enzymes (DUBs) [10-13].

These molecules destabilize p53, making it inert and no longer able to regulate tumor growth. Targeting the pathways that lead to p53 inactivation, such as inhibitors of the MDM2-p53 interaction, could be beneficial to improving treatments for the advanced stages of ovarian cancer [11,12]. Each subtype of ovarian cancer has a link to p53. Understanding which mechanism blocks p53 in each subtype and how to target that mechanism can lead to specialized treatment and increased survival for ovarian cancer.

Comparison of CCC and HGSC

Understanding the subtype of ovarian carcinoma that is present can help lead physicians toward specialized treatment plans for each patient. Each histological subtype has unique molecular abnormalities, separate risk factors, and differing treatment needs [5,14-16]. The two main subtypes of ovarian cancer, based on frequency and mortality, are High-Grade Serous Ovarian Cancer (HGSC) and Clear Cell Carcinoma (CCC). HGSC is the most aggressive subtype of the disease. As recently as 2017, HGSC accounted for approximately 70% of epithelial ovarian cancer cases, but had a 5-year survival rate that was less than 40% [1,2,4,17]. CCC accounted for approximately 10% of ovarian cancer cases overall and as much as 25% of cases in Asia [14]. CCC is notoriously hard to target, especially if diagnosed in the advanced stages, and the 3-year survival rate was only about 10% of the confirmed cases in 2016 [18,19]. If diagnosed in stage III-IV, CCC can be very difficult to treat, accounting for low survival.

Each form has unique precursor lesions and sites of origin. Until recently, it was thought that all subtypes arose from ovarian surface epithelium, but new evidence shows that each type originates from a different non-ovarian tissue [2]. HGSC may originate from precursor lesions in the fimbriae of the fallopian tubes [16,20]. This is supported by evidence that risk-reducing surgeries lower the prevalence of disease in healthy women with BRCA1 and BRCA2 mutations [3]. Whole-exome sequencing of HGSC patients also supports this conclusion [21]. CCC can arise in the ovary, endometrium, and the cervix and has been linked to endometriosis in many studies [3,5,15,22-24]. HGSC mitotic rate is high and most patients will present at high-stage, with advanced metastasis, while CCC is usually low-stage and mitoses are less frequent [14,25,26]. Patients with CCC are also younger than patients with HGSC on average [25]. These differences arise from differences in the biochemistry of each subtype.

Molecularly, the two subtypes have different mutations. HGSC cases have defects in BRCA1, BRCA2, and TP53, while CCC cases frequently lack these mutations [14,23]. CCC patients commonly have mutations in ARID1A and PI3K, which are two genes involved with chromosome remodeling and cell growth and division [5,19,26,27]. MDM2 (Murine Double Minute 2), a ubiquitin ligase, has significantly higher expression in CCC than in HGSC. This overexpression of MDM2 blocks wild-type p53 function, allowing cancerous cell growth to continue uninhibited and leads to poor overall survival in CCC [18,25]. In HGSC, ADRM1, which encodes part of the 19S regulatory particle, is over expressed. Overexpression of ADRM1 is important for HGSC survival because it helps recognize and degrade the excess polyubiquitinated proteins produced by the cancer, allowing it to continue creating more proteins as it rapidly metastasizes [28]. These pathways and how they may be targeted are explained in further detail below.

Biochemical Pathways

MDM2 and p53

Dysfunction of p53 has important implications for both HGSC and CCC, though each is caused by a different mechanism. In HGSC, p53 does not function to regulate tumor growth due to the TP53 mutation seen in greater than 90% of HGSC cases [1,5,29,30]. In CCC, patients have a wild-type TP53 gene, but normal function is inhibited by DUB molecules. Recent evidence has shown that ovarian cancer patients without TP53 mutation were likely to have p53 dysfunction associated with copies of the E3 ubiquitin ligase MDM2 [7]. MDM2 plays a crucial role in the degradation and regulation of p53 in the body. In normal cells, wild-type p53 is short lived and acts to suppress tumor formation and inhibit cell growth [31,32]. It can bind to specific DNA sequences in order to activate the transcription of genes involved with stress and tumor suppression. One of the genes that p53 binds to is the MDM2 gene. The p53 protein can bind to the MDM2 gene in order to regulate its level of transcription, while MDM2 can in return bind to p53 to regulate its level of activity in the body [33,34]. Generally, MDM2 activity will be seen an hour after p53 in order to slow down the p53 response. MDM2 acts as a negative regulator for p53, inhibiting and suppressing p53 function via proteasome-mediated degradation and terminating the p53 signal in normally functioning cells [35,36]. These molecules are tightly controlled and inversely correlated; when MDM2 levels rise, p53 levels lower [18,31]. In certain cancers, MDM2 overexpression creates such a strong negative feedback signal that it inhibits normal function of p53 (Figure 1). This overexpression occurs in CCC ovarian cancer.

Citation: Werts S and Ye J. Differential Impact of the Ubiquitin-Proteasome System on Clear Cell Carcinoma and High-Grade Serous Ovarian Cancer. Austin Biochem. 2018; 3(1): 1015.