Types of Cancer Modification
Types of Cancer Modification
Understanding the central dogma of molecular biology (DNA replication, transcription, post-translation, and translation into proteins) is critical in understanding carcinogenesis and the mechanisms in which cancer is manifested. As such, post-translational modification (PTM) has gained clinical attention due to its role in carcinogenesis. PTM is a covalent enzyme-mediated modification of proteins that occurs after the biosynthesis of proteins (Chou, 2019). PTMs include acetylation, methylation, phosphorylation, SUMOylation, and ubiquitination. Further, the regulation of PTMs is via enzymes called writers and erasers, which add and remove PTMs from histones, respectively. Writers include histone kinases, histone methyltransferases (HMTs), and histone acetyltransferases (HATs) that add phosphoryl, methyl, and acetyl marks, respectively. Erasers include histone phosphatases, histone demethylases (HDMs), and histone deacetylases (HDACs) that remove phosphoryl, methyl, and acetyl marks, respectively. These enzymes co-interact to influence cellular processes like replication, transcription, and repair (Khan, 2015).
Acetylation is the addition of acetyl groups at lysine residues on histone tails. It is a reversible modification controlled by HATs and histone deacetylases (HDACs). It promotes the opening of chromatin to facilitate active transcription (Zhao & Shilatifard, 2019). Recent discoveries have reported that histone acetylation functions to regulate intracellular pH (pHi). Consequently, many cancers demonstrate low pHi and reduced levels of acetylation, which relates to poor clinical outcomes (Audia & Campbell, 2016). Further, over-acetylation involving proto-oncogenes activates gene expression, whereas under-acetylation causes gene silencing and suppresses tumor expression.
Methylation is the addition of methyl groups in the nitrogen atoms of arginine and lysine residues. Histone methylation is a transcriptional regulatory mechanism that influences chromatin structure and interacts with transcriptional factors (initiation and elongation) to affect the processing of RNA. Methylation is closely regulated by various methyltransferase writers and demethylase erasers, which interact to add or remove specific methyl groups for gene expression and stability. Abnormal levels of histone methylation have been linked to tumorigenesis. For instance, overexpression of histone methyltransferase KMT1C has been associated with lung cancer, while overexpression of histone demethylase KDM1A has been connected to prostate and bladder cancer.
Figure 1: Post-translational Modification
Note: Global Histone Post-Translational Modifications and Cancer: Biomarkers For Diagnosis, Prognosis, and Treatment (p. 335) by Shafqat Khan. (2015).
Phosphorylation (addition of phosphoryl groups) is a reversible modification that controls various cellular processes that occur through phosphatases and protein kinases. These cellular processes include cell division, protein synthesis, signal transduction, cell growth, and aging. Mainly, protein kinases regulate signal transduction, and their overexpression or malfunction is associated with most cancer cells (Sharma et al., 2019). Moreover, phosphorylation negatively charges histone tails, changing the chromatin structure and their interaction with transcription factors. For instance, phosphorylation of histone HES10 is associated with chromatin condensation during mitosis, thus regulating transcription positively.
Ubiquitination degrades and recycles proteins in a conserved and dynamic multi-process. It takes place at lysine residues on histones. Significantly, it is involved in repairing damaged DNA and activating NFkB inflammatory response. Often, ubiquitination is triggered by phosphorylation. Enzymes involved in ubiquitination include ligases, conjugating enzymes, and activating enzymes. Aberrant expression of these enzymes, including deubiquitination enzymes (DUBs), facilitates the signalling of specific oncogenes, resulting in metastasis and cancer progression.
Small ubiquitin-like modifiers (SUMOs) are family proteins that are attached to lysine residues of target proteins. The SUMO pathway regulates the cell cycle, apoptosis, cellular signalling, gene expression, and DNA damage repair. This regulation by SUMOs is called SUMOylation. SUMOylation also controls the expression or repression of many tumour suppressors and oncogenes. For instance, modification of the tumour suppressor gene BRCA1, associated with breast and ovarian cancers, is mediated via SUMOylation.
Audia, J., & Campbell, R. (2016). Histone Modifications and Cancer. Cold Spring Harbor Perspectives in Biology, 8(4), a019521. https://doi.org/10.1101/cshperspect.a019521
Chou, K. (2019). Progresses in Predicting Post-translational Modification. International Journal of Peptide Research and Therapeutics, 26(2), 873. https://doi.org/10.1007/s10989-019-09893-5
Khan, S. (2015). Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis, and treatment? World Journal of Biological Chemistry, 6(4), 335. https://doi.org/10.4331/wjbc.v6.i4.333
Sharma, B., Prabhakaran, V., Desai, A., Bajpai, J., Verma, R., & Swain, P. (2019). Post-Translational Modifications (PTMs), from a Cancer Perspective: An Overview. Oncogene, 2(3). https://doi.org/10.35702/onc.10012
Zhao, Z., & Shilatifard, A. (2019). Epigenetic modifications of histones in cancer. Genome Biology, 20(1). https://doi.org/10.1186/s13059-019-1870-5
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