The role of DOT1L in the proliferation and prognosis of gastric cancer

Abstract

Background: Disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of H3K79, was observed to be amplified and overexpressed in certain malignancies. This work was aimed at investigating the differences in DOT1L expression and its regulatory mechanism in gastric cancer (GC) and healthy samples. Methods: Immunohistochemistry was used to detect DOT1L levels in 101 cases of GC and marching adjacent normal tissues. DOT1L was inhibited by small interfering RNA (siRNA) and EPZ5676; a targeting drug. The ability of cells to proliferate were checked by cell counting kit-8 (CCK-8) and clone formation assays, with flow cytometry for observing the cell cycle. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot revealed the gene and protein profiles. Finally, the outcome of EPZ5676 administration was checked on a murine model. Results: The expression of DOT1L is significantly increased in gastric malignant tumors that is related to the degree of differentiation, lymph node metastasis and TNM staging. DOT1L serves as an independent marker for the prognosis of overall survival (OS) with high levels implying worse prognosis. In addition, DOT1L regulates cyclin-dependent kinase (CDK) 4 (CDK4) and CDK6 through H3K79me2, which leads to a change in the cell cycle at G 1 , thereby affecting the proliferation of tumors in vitro and in vivo. Conclusions: This is a first clinical demonstration of the applicability of DOT1L overexpression in gastric tumors. The work is suggestive of altered proliferation of cells by DOT1L via regulating cyclins and H3K79 methylation. This indicates the role of DOT1L in the prognosis and possible medical intervention of GC.

DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

“…These data provide evidence to demonstrate that DOT1L upregulation upon OIS induction occurs in multiple models and cell types and is associated with increased IL1A . Indeed, previous reports have shown that DOT1L suppresses senescence in yeast ( Kozak et al, 2010 ) and plays a protective role in UV-induced melanomagenesis ( Zhu et al, 2018 ), although other studies have shown the opposite ( Barry et al, 2009 ; Jones et al, 2008 ; Kim et al, 2012 ; Nassa et al, 2019 ; Roidl et al, 2016 ; Song et al, 2020 ; Yang et al, 2019 ; Zhang et al, 2014 ), suggesting that DOT1L activity and 1H3K79 methylation are context dependent. The discrepancy between these studies is not clear; it is possible that this is an inherent distinction between model systems.…”

DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

“…Indeed, DOT1, the yeast homolog of DOT1L, suppresses senescence (Kozak et al, 2010), and DOT1L plays a protective role in UV-induced melanomagenesis (Zhu et al, 2018). In contrast, other studies have associated decreased H3K79 methylation and DOT1L expression with loss of proliferation and senescence (Barry et al, 2009;Jones et al, 2008;Kim et al, 2012;Nassa et al, 2019;Roidl et al, 2016;Song et al, 2020;Yang et al, 2019;Zhang et al, 2014). The discrepancy between these studies is not clear.…”

<p>Mutational Characterization and Potential Prognostic Biomarkers of Chinese Patients with Esophageal Squamous Cell Carcinoma</p>

“…The mutation of FOS is reportedly associated with poor prognosis in colorectal cancer, 55 and high expression of DOT1L and VEGFA indicates poor prognosis in many cancers, such as lung cancer, gastric cancer, and clear cell renal cell carcinoma. 56–59 These reports imply that mutation of these genes is potentially associated with the prognosis of ESCC as well. However, we failed to detect a correlation between these mutations and the disease-free survival of ESCC.…”

“…The mutation of FOS is reportedly associated with poor prognosis in colorectal cancer, 55 and high expression of DOT1L and VEGFA indicates poor prognosis in many cancers, such as lung cancer, gastric cancer, and clear cell renal cell carcinoma. [56][57][58][59] These reports imply that mutation of these genes is potentially associated with the Figure 6 The correlation between metastatic lymph node status and the prognosis of ESCC patients. (A) The differential analysis of disease-free survival of patients with and without metastatic lymph nodes.…”