Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors
Abstract
Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with histone deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, histone deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53.
Introduction
The p53 tumor suppressor is mutated in 50% of human cancers ( 1). Although mutant p53 renders cancer cells resistant to certain anticancer drugs, it is also a potential cancer-specific target for pharmacologic intervention ( 2– 4). Given that mutant p53 is highly overexpressed, its sudden reactivation may be very toxic for a cell. Reintroduction of wild-type (wt) p53 by adenoviruses (Ad-p53) is predominantly cytotoxic to cancer cells that lack wt p53 (mutant p53 and null; ref. 5). However, it is currently technically impossible to introduce wt p53 all tumor cells. Another strategy is to reactivate mutant p53 using small molecular therapeutic agents that change conformation of mutant p53 ( 2– 4). Although several compounds were described, their selectivity, specificity, and mechanism of action are still unclear ( 2, 6). Another strategy is to deplete mutant p53. For example, Hsp90-active agents (e.g., geldanamycin) moderately decrease mutant p53 ( 7). Although depletion of mutant p53 per se cannot and does not restore p53 functions, it may abolish dominant-positive effects ( 8, 9). https://cancerres.aacrjournals.org/content/65/16/7386
impact factor oncotarget Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
When public speak of today’s medicine, accuracy plays one of the most important roles and people’s lives are directly dependent on it. Hereby, any researches pertaining to medicine are necessary to meet the highest standards. The problem nowadays is that any outcomes of researches can be published online and used as a reference without being thoroughly checked and validated. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and tried to create an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been established back in 2010. The main principle of this journal is based on Altmetric scores that are used as a quality measure. That allows both readers and authors to validate publications with Altmetric Article Reports that generate “real-time feedback containing data summary related to a particular publication.” Oncotarget website has a full publications list with corresponding scores above 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it creates the necessary assistance to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was released back in 2018 by Oncotarget and written by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are willing to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hence, the article about melanoma, was utilized for citations in different news articles 69 times. In addition, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This study has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive helpful scientific facts. Oncotarget is happy to have the ability to share with online customers this highly appreciated and top-quality information, that is trustworthy and reliable.
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