Implications of Transglutaminase-Mediated Protein Serotonylation in the Epigenetic Landscape, Small Cell Lung Cancer, and Beyond
Jason Lin1,2, Shang-Chuen Wu3
1Laboratory of Clinical Genomics, Chiba Cancer Center Research Institute, Chiba Cancer Center, Chiba 260-8717, Japan.
Abstract:
In the case of small-cell lung carcinoma, the highly metastatic nature of the disease and the propensity for several chromatin modifiers to harbor mutations suggest that epigenetic manipulation may also be a promising route for oncotherapy, but histone deacetylase inhibitors on their own do not appear to be particularly effective, suggesting that there may be other regulatory parameters that dictate the effectiveness of vorinostat's reversal of histone deacetylation. Recent discoveries that serotonylation of histone H3 alters the permissibility of gene expression have led to renewed attention to this rare modification, as facilitated by transglutaminase 2, and at the same time introduce new questions about whether this modification belongs to a part of the concerted cohort of regulator events for modulating the epigenetic landscape. This review explores the mechanistic details behind protein serotonylation and its possible connections to the epigenome via histone modifications and glycan interactions and attempts to elucidate the role of transglutaminase 2, such that optimizations to existing histone deacetylase inhibitor designs or combination therapies may be devised for lung and other types of cancer.
Insights
Epigenetic therapies show promise for small-cell lung carcinoma, but histone deacetylase inhibitors alone are insufficient. Protein serotonylation, mediated by transglutaminase 2, offers a new target for enhancing cancer treatment efficacy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Small-cell lung carcinoma (SCLC) is highly metastatic, with frequent mutations in chromatin modifiers.
- Histone deacetylase inhibitors (HDACis) show limited efficacy alone in SCLC, suggesting other regulatory mechanisms are involved.
- Protein serotonylation, a histone modification, influences gene expression and is facilitated by transglutaminase 2 (TG2).
Purpose of the Study:
- To explore the mechanistic details of protein serotonylation.
- To investigate the connection between protein serotonylation, histone modifications, and glycan interactions.
- To elucidate the role of TG2 in epigenetic regulation for potential cancer therapy optimization.
Main Methods:
- Literature review of protein serotonylation and epigenetic mechanisms.
- Analysis of existing data on HDAC inhibitors and their limitations.
- Exploration of TG2's function in histone modification and gene expression.
Main Results:
- Protein serotonylation represents a rare but significant epigenetic modification impacting gene expression permissibility.
- TG2 facilitates histone H3 serotonylation, potentially influencing the epigenetic landscape.
- The interplay between serotonylation, histone modifications, and glycan interactions requires further investigation.
Conclusions:
- Understanding protein serotonylation and TG2's role may lead to improved HDAC inhibitor designs or novel combination therapies for SCLC and other cancers.
- Targeting protein serotonylation could offer a new avenue for epigenetic oncotherapy.
- Further research is needed to fully elucidate the therapeutic potential of modulating protein serotonylation.
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