CBP Mediated DOT1L Acetylation Confers DOT1L Stability and Promotes Cancer Metastasis

Overview

Journal Theranostics

Date 2020 Feb 12

PMID 32042335

Citations 24

Authors

Chaohua Liu

Qiaoyan Yang

Qian Zhu

Xiaopeng Lu

Meiting Li

Tianyun Hou

Zhiming Li

Ming Tang

Yinglu Li

Hui Wang

Yang Yang

Haiying Wang

Ying Zhao

He Wen

Xiangyu Liu

Zebin Mao

Wei-Guo Zhu

Affiliations

Soon will be listed here.

Abstract

: DOT1L regulates various genes involved in cancer onset and progression by catalyzing H3K79 methylation, but how DOT1L activity itself is regulated is unclear. Here, we aimed to identify specific DOT1L post-translational modifications that might regulate DOT1L activity and thus impact on colorectal cancer (CRC) progression. : We conducted affinity purification and mass spectrometry to explore DOT1L post-translational modifications. We then established transwell migration and invasion assays to specifically investigate the role of DOT1L(K358) acetylation on CRC cellular behavior and a bioluminescence imaging approach to determine the role of DOT1L(K358) acetylation in CRC metastasis . We performed chromatin immunoprecipitation to identify DOT1L acetylation-controlled target genes. Finally, we used immunohistochemical staining of human tissue arrays to examine the relevance of DOT1L(K358) acetylation in CRC progression and metastasis and the correlation between DOT1L acetylation and CBP. : We found that CBP mediates DOT1L K358 acetylation in human colon cancer cells and positively correlates with CRC stages. Mechanistically, DOT1L acetylation confers DOT1L stability by preventing the binding of RNF8 to DOT1L and subsequent proteasomal degradation, but does not affect its enzyme activity. Once stabilized, DOT1L can catalyze the H3K79 methylation of genes involved in epithelial-mesenchymal transition, including and . An acetylation mimic DOT1L mutant (Q358) could induce a cancer-like phenotype characterized by metastasis and invasion. Finally, DOT1L(K358) acetylation correlated with CRC progression and a poor survival rate as well as with high CBP expression. : DOT1L acetylation by CBP drives CRC progression and metastasis. Targeting DOT1L deacetylation signaling is a potential therapeutic strategy for DOT1L-driven cancers.

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