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Decrease in Lymphoid Specific Helicase and 5-hydroxymethylcytosine Is Associated with Metastasis and Genome
Jiantao Jia1,2,3,4, Ying Shi1,3, Ling Chen1,3
1Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China.
Abstract:
DNA methylation is an important epigenetic modification as a hallmark in cancer. Conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) family enzymes plays an important biological role in embryonic stem cells, development, aging and disease. Lymphoid specific helicase (LSH), a chromatin remodeling factor, is regarded as a reader of 5-hmC. Recent reports show that the level of 5-hmC is altered in various types of cancers. However, the change in 5-hmC levels in cancer and associated metastasis is not well defined. We report that the level of 5-hmC was decreased in metastatic tissues of nasopharyngeal carcinoma, breast cancer, and colon cancer relative to that in non-metastasis tumor tissues. Furthermore, our data show that TET2, but not TET3, interacted with LSH, whereas LSH increased TET2 expression through silencing miR-26b-5p and miR-29c-5p. Finally, LSH promoted genome stability by silencing satellite expression by affecting 5-hmC levels in pericentromeric satellite repeats, and LSH was resistant to cisplatin-induced DNA damage. Our data indicate that 5-hmC might serve as a metastasis marker for cancer and that the decreased expression of LSH is likely one of the mechanisms of genome instability underlying 5-hmC loss in cancer.
Insights
The epigenetic mark 5-hydroxymethylcytosine (5-hmC) decreases in metastatic cancers. Lymphoid specific helicase (LSH) loss contributes to genome instability and 5-hmC reduction in cancer.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- DNA methylation, specifically 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) conversion by TET enzymes, is a critical epigenetic modification in development and disease.
- Lymphoid specific helicase (LSH), a chromatin remodeler, interacts with 5-hmC, and altered 5-hmC levels are observed in various cancers.
Purpose of the Study:
- To investigate the role of 5-hmC in cancer metastasis and the underlying mechanisms involving LSH and TET enzymes.
- To determine if 5-hmC levels change in metastatic versus non-metastatic tumor tissues.
- To elucidate the relationship between LSH, TET2, and microRNAs in regulating 5-hmC and genome stability.
Main Methods:
- Comparative analysis of 5-hmC levels in metastatic and non-metastatic tissues from nasopharyngeal, breast, and colon cancers.
- Investigation of the interaction between LSH and TET family enzymes (TET2, TET3).
- Assessment of LSH's effect on TET2 expression via microRNA silencing (miR-26b-5p, miR-29c-5p).
- Evaluation of LSH's role in genome stability by analyzing its impact on satellite expression and 5-hmC levels in pericentromeric regions.
- Assessment of LSH's resistance to cisplatin-induced DNA damage.
Main Results:
- 5-hmC levels were significantly decreased in metastatic tissues compared to non-metastatic tumor tissues across multiple cancer types.
- TET2 was found to interact with LSH, and LSH promoted TET2 expression by suppressing miR-26b-5p and miR-29c-5p.
- LSH enhanced genome stability by reducing satellite expression through modulation of 5-hmC levels in pericentromeric repeats.
- LSH exhibited resistance to cisplatin-induced DNA damage.
Conclusions:
- Decreased 5-hmC levels correlate with cancer metastasis, suggesting its potential as a biomarker.
- Reduced LSH expression is a potential mechanism driving genome instability and 5-hmC loss in cancer.
- The LSH-TET2-microRNA axis plays a crucial role in maintaining 5-hmC homeostasis and genome integrity in cancer cells.
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