Targeting Epigenetic Regulators for Endometrial Cancer Therapy: Its Molecular Biology and Potential Clinical Applications

Round 1

Reviewer 1 Report

This reviewer has only few observations: 

• in 2.2 DNA methylation and EC, few examples are reported about EC type II while a good information level is discussed about EC type I. 
• In 4.1 it is unclear the statement: "When HDAC inhibitors are administered to EC cell lines, they reduced both histone acetylation and DNA methylation signals".
• In 4.2.1 “A previous study on vorinostat, which has already been used clinically in other cancers...” it sounds criptic.
• More in geeral, a focus on in vivo experiment could be appropriate for this review. 

Author Response

Reviewer 1

 

This reviewer has only few observations: 

 

Comment1

• in 2.2 DNA methylation and EC, few examples are reported about EC type II while a good information level is discussed about EC type I. 

 

Reply: We appreciate your critical comments and useful suggestions. According to previous reports, promotor hypermethylation is more frequently reported in type I EC than type II EC. In fact, TCGA reported that the copy-number high group EC (included in type II EC) had minimal DNA methylation changes. The above consideration was added to lines 147-152. However, there are a few reports regarding type II EC. We have also added this to lines 179-185.

 

Comment2　and Comment3

• In 4.1 it is unclear the statement: "When HDAC inhibitors are administered to EC cell lines, they reduced both histone acetylation and DNA methylation signals".
• In 4.2.1 “A previous study on vorinostat, which has already been used clinically in other cancers...” it sounds criptic.

 

Reply: We appreciate your critical comments and useful suggestions. We have revised the text in more detail (Lines 382-387 and Lines 417-419).

 

Comment4

• More in geeral, a focus on in vivo experiment could be appropriate for this review. 

 

Reply: We thank you for carefully reviewing our manuscript. We have revised the manuscript accordingly (Lines 382-387 and Lines 419-421).

Reviewer 2 Report

The authors performed a narrative review about the role of DNA methylation and histone modification in endometrial cancer (EC), the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials. The manuscript is well written. However, the authors referred to the Bokhman’s classification of EC. Such a classification has been overtaken by new findings from The Cancer Genome Atlas Research Network (TCGA)/ ProMisE. TCGA/ProMisE have shown that endometrial carcinoma may be reclassified in four molecular prognostic groups of EC.The authors should refer to the novel molecular classifier. In particular, recently, several studies and systematic reviews and meta-analyses have assessed this topic and should be considered in the manuscript. In addition, the authors referred to EC treatment in a generic way. The authors should specify the treatment and staging.

Author Response

Reviewer 2

Comment1

・The authors performed a narrative review about the role of DNA methylation and histone modification in endometrial cancer (EC), the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials. The manuscript is well written. However, the authors referred to the Bokhman’s classification of EC. Such a classification has been overtaken by new findings from The Cancer Genome Atlas Research Network (TCGA)/ ProMisE. TCGA/ProMisE have shown that endometrial carcinoma may be reclassified in four molecular prognostic groups of EC.The authors should refer to the novel molecular classifier. In particular, recently, several studies and systematic reviews and meta-analyses have assessed this topic and should be considered in the manuscript. In addition, the authors referred to EC treatment in a generic way. The authors should specify the treatment and staging.

 

Reply: We appreciate your critical comments and useful suggestions. As you mentioned, new molecular subtypes from TCGA are also important. We have revised the manuscript as suggested (Lines 41-49, 147-150, 155-156 and 162-164).

In addition, as you pointed out, we revised the manuscript regarding the treatment for EC (Lines 50-58).

 

Reviewer 3 Report

As described by Futaba Inoue et al,  epigenetic lesions could potentially serve as detection biomarkers for EC and in my opinion it could be useful to dedicate a specific subchapter to epigenetic in the diagnosis in EC, integrating with few additional references (for example  Liew, PL., Huang, RL., Wu, TI. et al. Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings. Clin Epigenet 11, 170 (2019). https://doi.org/10.1186/s13148-019-0765-3).

DNA methylation depends on environmental risk factors and since has been reported that ,among risk factors of EC. obesity influences DNA methylation (Nagashima, M., Miwa, N., Hirasawa, H. et al. Genome-wide DNA methylation analysis in obese women predicts an epigenetic signature for future endometrial cancer. Sci Rep 9, 6469 (2019). https://doi.org/10.1038/s41598-019-42840-4) it could be useful to discuss this aspect in the text.

Author Response

・As described by Futaba Inoue et al, epigenetic lesions could potentially serve as detection biomarkers for EC and in my opinion it could be useful to dedicate a specific subchapter to epigenetic in the diagnosis in EC, integrating with few additional references (for example Liew, PL., Huang, RL., Wu, TI. et al. Combined genetic mutations and DNAmethylated genes as biomarkers for endometrial cancer detection from cervical scrapings. Clin Epigenet 11, 170 (2019). https://doi.org/10.1186/s13148-019-0765-3). DNA methylation depends on environmental risk factors and since has been reported that ,among risk factors of EC. obesity influences DNA methylation (Nagashima, M., Miwa, N., Hirasawa, H. et al. Genome-wide DNA methylation analysis in obese women predicts an epigenetic signature for future endometrial cancer. Sci Rep 9, 6469 (2019). https://doi.org/10.1038/s41598-019-42840-4) it could be useful to discuss this aspect in the text.

 

Reply: We appreciate your critical comments and useful suggestions. We have dedicated a specific subchapter to epigenetics in the diagnosis in EC, integrated with the references you recommended (Lines 206-208). In addition, we have mentioned that DNA methylation depends on environmental risk factors using the reference you suggested as an example (Lines 213-217).

 

Reviewer 4 Report

This is the most complete review on the role of epigenetic regulators and their targeting potential in endometrial cancer. It was very instructive to me and will be definitively useful for the scientific community.

Author Response

We appreciate your comment.