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Loss of nuclear localization of TET2 in colorectal cancer
Yuji Huang1,2, Guanghui Wang1,2, Zhonglin Liang1,2
1Department of colorectal and anal surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Abstract:
5-Hydroxymethylcytosine (5hmC) is lost in multiple human cancers, including colorectal cancer (CRC). Decreased ten-eleven translocation 1 (TET1) messenger RNA (mRNA), but not other two TET family members, has been observed in the colorectal cancer and is crucial for colorectal cancer initiation. Here, we show that nuclear localization of TET2 was lost in a significant portion of CRC tissues, in association with metastasis. In CRC cells, nuclear expression of TET2 were absent but not TET3. Nuclear export inhibitor can increase the 5hmC level in CRC cells, probably through regulating TET2. Our results indicate a new mechanism of TET2 dysregulation in colorectal cancer.
Insights
Loss of 5-hydroxymethylcytosine (5hmC) is linked to colorectal cancer (CRC). This study reveals TET2 dysregulation in CRC cells, impacting nuclear localization and potentially increasing 5hmC levels via nuclear export inhibition.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Oncology
- Genetics and Genomics
Background:
- 5-Hydroxymethylcytosine (5hmC) is a crucial epigenetic marker frequently lost in human cancers, including colorectal cancer (CRC).
- While TET1 mRNA is decreased in CRC, the role of other TET family members, particularly TET2, in CRC pathogenesis remains less understood.
- Understanding epigenetic alterations in CRC is vital for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the role and mechanism of TET2 dysregulation in colorectal cancer.
- To determine the impact of altered TET2 localization on 5hmC levels in CRC cells.
- To explore potential therapeutic targets related to TET2 function in CRC.
Main Methods:
- Analysis of TET2 nuclear localization in colorectal cancer tissues and cell lines.
- Assessment of 5hmC levels in CRC cells.
- Investigation of nuclear export inhibition effects on TET2 and 5hmC in CRC cells.
Main Results:
- Nuclear localization of TET2 was significantly lost in a subset of CRC tissues, correlating with metastasis.
- CRC cells exhibited absent nuclear TET2 expression, unlike TET3.
- Inhibition of nuclear export in CRC cells led to increased 5hmC levels, suggesting TET2 regulation.
Conclusions:
- TET2 dysregulation, specifically loss of nuclear localization, represents a novel mechanism in colorectal cancer development.
- Altered TET2 function contributes to the loss of 5hmC in CRC.
- Targeting TET2 nuclear export may offer a potential therapeutic approach for colorectal cancer.
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