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Natural Merosesquiterpenes Activate the DNA Damage Response via DNA Strand Break Formation and Trigger Apoptotic Cell Death in p53-Wild-Type and Mutant Colorectal Cancer
Review

Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

1
Department of Toxicology, University Medical Center, 55131 Mainz, Germany
2
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, 55128 Mainz, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Ellen Kapiteijn
Cancers 2021, 13(16), 4072; https://doi.org/10.3390/cancers13164072
Received: 24 June 2021 / Revised: 3 August 2021 / Accepted: 10 August 2021 / Published: 13 August 2021
(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)
Colorectal cancer (CRC) belongs to the most common cancer types. It is well known that half of all CRC possess missense mutations in the TP53 tumor suppressor gene. However, the entire signaling cascade upstream and downstream of the p53 protein may also contribute to CRC development, if relevant players in this signaling cascade lost their function. Besides p53 loss-of-function by mutations, epigenetic changes (DNA methylation, post translational modifications of histones, micro-RNAs) play a vital role in CRC development. In the present review, we concentrated on the epigenetic modifications related to the entire p53 signal transduction cascade upstream and downstream of p53. Indeed, numerous epigenetic aberrations influence the tumor suppressor function of p53 independent of missense mutations. Thus, the role of p53 for CRC development, therapy response and survival prognosis of patients may be much more complex than predicted earlier. Hence, we are in need to use novel diagnostic methods that are capable of evaluating the genetic and epigenetic changes in the “p53 signalome”, so that diagnosis and management of CRC will improve.
Colorectal cancer (CRC) belongs to the most common tumor types, and half of all CRC harbor missense mutations in the TP53 tumor suppressor gene. In addition to genetically caused loss of function of p53, epigenetic alterations (DNA methylation, histone modifications, micro-RNAs) contribute to CRC development. In this review, we focused on epigenetic alterations related to the entire p53 signaling pathway upstream and downstream of p53. Methylation of genes which activate p53 function has been reported, and methylation of APC and MGMT was associated with increased mutation rates of TP53. The micro-RNA 34a activates TP53 and was methylated in CRC. Proteins that regulate TP53 DNA methylation, mutations, and acetylation of TP53-related histones were methylated in CRC. P53 regulates the activity of numerous downstream proteins. Even if TP53 is not mutated, the function of wildtype p53 may be compromised if corresponding downstream genes are epigenetically inactivated. Thus, the role of p53 for CRC development, therapy response, and survival prognosis of patients may be much more eminent than previously estimated. Therefore, we propose that novel diagnostic devices measuring the entirety of genetic and epigenetic changes in the “p53 signalome” have the potential to improve the predictive and prognostic power in CRC diagnostics and management. View Full-Text
Keywords: acetylation; carcinogenesis; methylation; micro-RNA; oncogene; signal transduction; tumor suppressor acetylation; carcinogenesis; methylation; micro-RNA; oncogene; signal transduction; tumor suppressor
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MDPI and ACS Style

Tomicic, M.T.; Dawood, M.; Efferth, T. Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma. Cancers 2021, 13, 4072. https://doi.org/10.3390/cancers13164072

AMA Style

Tomicic MT, Dawood M, Efferth T. Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma. Cancers. 2021; 13(16):4072. https://doi.org/10.3390/cancers13164072

Chicago/Turabian Style

Tomicic, Maja T., Mona Dawood, and Thomas Efferth. 2021. "Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma" Cancers 13, no. 16: 4072. https://doi.org/10.3390/cancers13164072

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