UHRF I Inhibitors
Cancer is one of the major causes of death across the globe. In addition to its high mortality rate, cancer has serious economic and social implications. At the same time, cancer kills many people in their productive years, robbing the country of important professionals such as doctors, teachers, nurses, engineers, drivers, and law enforcement officers, among others. More importantly, the current cancer treatment modalities are not very effective in eradicating this condition and preventing it from reemerging. More importantly, these therapeutics are only significantly effective when cancer is detected early. Thus, there is a need for the development of more effective ways of treating various types of cancer, especially the rare ones and those that are detected late.
Over the recent past, UHFR1 inhibitors have received massive attention from researchers since it is believed that they present a rare opportunity for the development of more effective treatment modalities for various types of cancer. Epigenetic changes, which include histone modifications as well as aberrant DNA methylation, are a crucial element for the development of tumors. One of the common traits of cancer cells is that they have DNA methylation-associated changes.
UHRFI inhibitors are considered to be master regulators of epigenome because of their role in the coordination of histone modifications and DNA methylation. At the moment, there is a strong correlation between the overexpression of UHRFI and tumorigenesis. Aberration in UHRFI expression is correlated to the aggressiveness of different types of human malignancies, including breast cancer, gastric cancer, cervical cancer, lung cancer, and hepatocellular carcinoma. The overrepresentation of UHRFI in these cancers is very clear. More importantly, the depletion of these inhibitors can inhibit the invasion and growth of cancer cells. At the same time, it is highly likely that UHRFI may play the role of potential biomarkers for the diagnosis and prognosis of cancer. At the same time, UHRFI mediates the repairing of damaged DNA which makes cancerous cells to resist cytocidal drugs. Thus, a thorough understanding of the working of the UHFRI inhibitors at the molecular level is crucial in the development of cancer therapeutics. Several studies have shown that UHRF 1 can act as cancer drug target. The silencing or knockdown effects of UHFR1 result in increased apoptosis and reduced proliferation in cancer cells. UHRFI operates in different ways. As far as ectopic expression is concerned, UHRFI encourage the proliferation of cancer cells. On the other hand, UHRFI knockdown encourages apoptosis in cancer cells, cell cycle arrest, and DNA damage response.
Discussion
My focus paper is titled “UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells” authored by Niinuma et al. UHFR1 is expected to maintain DNA methylation without being biased towards any specific sets of genes. However, it is still unclear the role played by UHFRI inhibitors in the silencing of large sets of tumor-causing genes. This study aimed at examining how the UHRF1 is involved in gene silencing and DNA methylation as far as the cancer of colon is concerned. Colon cancer cells were temporary infected with siRNAs-targeting UHRF1. The resulting DNA methylation was evaluated with the use of the bisulfite pyrosequencing and dot blots assays. The extent of gene expression was evaluated with the use of the RT-PCR method as well the employment of microarrays for gene expression. The colorectal cancer cells experienced rapid inducement of genome-wide DNA demethylation following UHRF1 depletion.
The researchers conducted primary research in which they used data availed by The Cancer Genome Atlas study. From this study, the researchers accessed RNA-seq data of primary normal colonic and colorectal cancer tissues. Fig 1 shows how the expression of UHFRI is significantly greater in colorectal cancer cells in comparison to normal colon cells. When colorectal cancer cells are grouped in accordance with their CIMP status, both CIMP-low and CIMP-high tumors exhibited relatively higher UHRFI expression in comparison to their counterparts from CIM-negative tumors. This finding suggests that there is a strong correlation between UHFRI and methylation of aberrant DNA in colorectal cancer cells as demonstrated by fig 1b.
In their study, Niinuma et al. came up with three conclusions. One of these conclusions states that the maintenance of DNA methylation in colorectal cancer cells is highly reliant on UHRF1 (1). Also, the researchers concluded that the depletion of UHRF1 rapidly triggers DNA demethylation although it is not adequate to reactive the silenced genes fully (Niinuma, Takeshi 1). The outcome of HDAC inhibition and UHRF1 depletion was a series of marked changes impacting gene expression profiles that culminated in the significant downregulation of the cell cycle-associated genes (Niinuma, Takeshi et al. 1). Evidently, the researchers feel that dual targeting of HDAC and UHFRI may be effective in the treatment of colorectal cancer.
To advance the current knowledge on the operation and qualities of UHFRI inhibitors, this paper proposes a research project aimed at enhancing the development of a more effective way of treating hepatocellular carcinoma cancer (HCC). HCC is very prevalent among certain minority groups. One of the common traits of HCC is that this type of cancer manifests itself through a relatively higher level of DNA hypomethylation, which is a significant contributor to tumor metastasis and progression. This paper proposes the development of compounds with the capacity to decrease DNA hypomethylation. The paper aims to capitalize on the ability of UHFRI to act as a master regulator of DNA methylome. When UHRF1 is overexpressed, it triggers increased DNA hypomethylation in hepatocellular carcinoma cells. More importantly, this paper will seek to develop small peptoids that hamper the protein-protein interaction (PPI) as far as the UHFRI-DNMT3A interaction is concerned. To pinpoint the compounds that hamper the PPI interactions of UHFRI and DNMT3A, the project aims to study the biological implications of the DNMT3A-UHF1 inhibitors by employing polymerase chain reaction on the cancer cells derived from the HCC tumors.
Kong et al. conducted a study in which they examined the UHFRI properties that are responsible for supporting the DNA methylation of the colorectal cancer cells and oncogenic features. This article suggests that the targeting of the UHRF1 protein can help in the development of DNA-demethylating therapeutic agents (Kong et al. 633). One part of this study that will be essential in the proposed project is where it describes the effects of the disruption of UHRF1 DNA hemimethylated binding domains in impairing oncogenic traits of colorectal cancer cell cells. According to Kong et al., the maintenance of DNA methylation anomalies associated with UHFR1 contributes to several oncogenic traits associated with colorectal cancer cells (642). This article implies that the inhibition of the interaction between UHFRI and DNMT3A presents a promising opportunity for the development of more effective methods for the management of HCC. Also, the article demonstrates that it is possible to pinpoint the specific compounds that inhibit the interactions between UHFR1 and DNMT3A. In their study, Giovinazzo et al. developed a high-throughput TR-FRET assay for screening inhibitors that have the capacity to disrupt the interaction between hemimethylated DNA and UHRF1-SRA domain. Using this tool, the researchers identified 7 compounds for UHRF1-SRA inhibitors from the Library of Pharmacologically Active Compounds (Giovinazzo et al. 3040). This article demonstrates that it is possible to focus on the compounds responsible for inhibiting UHFR1-DNMT3A interactions.
Works Cited
Giovinazzo, Hugh, et al. “A high-throughput screen of pharmacologically active compounds for inhibitors of UHRF1 reveals epigenetic activity of anthracycline derivative chemotherapeutic drugs.” Oncotarget, vol. 10, no. 32, 2019, pp. 3040-3050.
Kong, Xiangqian, et al. “Defining UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties.” Cancer Cell, vol. 35, no. 4, 2019, pp. 633-648.
Niinuma, Takeshi, et al. “UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells.” Clinical Epigenetics, vol. 11, no. 1, 2019, pp. 1-13.