From the journal RSC Chemical Biology Peer review history

30-Jun-2021

Dear Dr Yang:

Manuscript ID: CB-REV-04-2021-000075
TITLE: Targeting the RNA demethylase FTO for cancer therapy

Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below.

I have carefully evaluated your manuscript and the reviewers’ reports. As can be seen in the comments below, both reviewers found your work timely and comprehensive, that requires minor revisions.

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I look forward to receiving your revised manuscript.

Yours sincerely,
Professor Zaneta Nikolovska-Coleska
Associate Editor, RSC Chemical Biology

************

Reviewer 1

The review by Yang et al. summarized the known inhibitors and screening methods of FTO. FTO is the first reported m6A demethylase, and subsequent studies have shown that it is widely involved in various pathological processes. Taken together, I think this article is an excellent review for those who studies epigenetics. Before the manuscript is publishable, I have following suggestions or comments:
1. References have many formatting errors and should be carefully revised. For example, Ref 8 and 4, “Nature communications” is not abbreviated; The page number of Ref 49 are available; the page number of reference 83 is missing.
2. Kouzarides’ group reported the first selective Inhibitor (STM2457) of METTL3, and the author should cite this reference (DOI: 10.1038/s41586-021-03536-w) on page 27.

Reviewer 2

Reversible RNA modification is increasingly considered as an important mechanism to regulate gene expression at the post-transcriptional level. Among various RNA modifications, m6A has been extensively investigated. Accumulating evidence suggested that deregulation of RNA m6A modification contributes to the aberrant gene expression in cancers and thereby promotes cancer progression. FTO is the first RNA demethylase discovered in 2011, which opens up a new chapter of m6A biology. In this manuscript, Zhou et al., reviewed the current understanding of the role of FTO in human diseases, including cancers. The authors discussed the structural insights, strategies, and screening methods for the development of selective FTO inhibitors. The authors further discussed the property and mechanism of action of different currently available FTO inhibitors. In my opinion, this is a timely and comprehensive literature review. This review nicely summarized the key findings and future research direction related to the development of FTO inhibitors. The figure illustrations are also helpful to the readers. References are appropriately cited.
I only have some minor suggestions for the author’s consideration.
1. As indicated by the title, this review aims to discuss the potential of FTO inhibitors in cancer treatment. To this end, the authors should provide more detailed explanations on how FTO is deregulated in human cancers and how FTO deregulation contributes to human carcinogenesis.
2. Cancer is a heterogeneous disease. Up-regulation of FTO has been reported in some cancers, but on the other hand, FTO was down-regulated in other cancers. The applicability of FTO inhibitors in different cancer types should be discussed. In addition, intertumoral heterogeneity within the same type of cancer is also common. Is there any potential biomarker that can predict the treatment outcome of FTO inhibitors?
3. The target specificity of FTO and other RNA demethylases should be discussed. FTO-specific probes are definitely valuable for dissecting the molecular pathway regulated by FTO. However, in terms of cancer therapeutic, would pan-RNA demethylase inhibitors have any advantage?
4. The anticancer effects of FTO inhibitors in animal models should be highlighted.
5. It will be good to have a small paragraph to summarize the current limitations in the field and future perspectives.

This text has been copied from the PDF response to reviewers and does not include any figures, images or special characters.

July 15, 2021

Manuscript Title: Targeting the RNA demethylase FTO for cancer therapy
Manuscript ID: CB-REV-04-2021-000075

Dear Professor Nikolovska-Coleska,
Thank you so much for handling the above referenced manuscript. I write to submit our revised manuscript entitled “Targeting the RNA demethylase FTO for cancer therapy ” for publication as a review article in RSC Chemical Biology.
We have carefully read the reviewers’ comments and have revised our manuscript based on these constructive suggestions. And it has been very helpful in improving the quality of our manuscript. Please see the attached file for our point-by-point response to the specific comments.
We very much hope the revised manuscript may be suitable for publication in RSC Chemical Biology. I look forward to reading your comments.

Sincerely yours,

Dr Cai-Guang Yang, FRSC
Shanghai Institute of Materia Medica
Chinese Academy of Sciences
Shanghai 201203
China

Response to the comments from reviewers

July 15, 2021
Journal: RSC Chemical Biology
Manuscript ID: CB-REV-04-2021-000075
Title: "Targeting the RNA demethylase FTO for cancer therapy"

IN SUMMARY
We gratefully thank all the reviewers for the positive comments and constructive suggestions. We have carefully revised our manuscript based on these comments. Please see the attached file for our point-by-point response to the comments of reviewers.

POINT-BY-POINT RESPONSES TO REVIEWERS’ COMMENTS:

General Comments from Reviewer 1: The review by Yang et al. summarized the known inhibitors and screening methods of FTO. FTO is the first reported m6A demethylase, and subsequent studies have shown that it is widely involved in various pathological processes. Taken together, I think this article is an excellent review for those who studies epigenetics. Before the manuscript is publishable, I have following suggestions or comments:
Response: We thank the reviewer for the positive comments.

Comment 1 from Reviewer 1: References have many formatting errors and should be carefully revised. For example, Ref 8 and 4, “Nature communications” is not abbreviated; The page number of Ref 49 are available; the page number of reference 83 is missing.
Response: We thank the reviewer so much for raising these mistakes. We have carefully revised the format of all references, and corrected the errors that the reviewer mentioned.

Comment 2 from Reviewer 1: Kouzarides’ group reported the first selective Inhibitor (STM2457) of METTL3, and the author should cite this reference (DOI: 10.1038/s41586-021-03536-w) on page 27.
Response: The work of the recently reported METTL3 inhibitors has been added and discussed in Line 673-675, and the reference is also cited in our revision.

General Comments from Reviewer 2: Reversible RNA modification is increasingly considered as an important mechanism to regulate gene expression at the post-transcriptional level. Among various RNA modifications, m6A has been extensively investigated. Accumulating evidence suggested that deregulation of RNA m6A modification contributes to the aberrant gene expression in cancers and thereby promotes cancer progression. FTO is the first RNA demethylase discovered in 2011, which opens up a new chapter of m6A biology. In this manuscript, Zhou et al., reviewed the current understanding of the role of FTO in human diseases, including cancers. The authors discussed the structural insights, strategies, and screening methods for the development of selective FTO inhibitors. The authors further discussed the property and mechanism of action of different currently available FTO inhibitors. In my opinion, this is a timely and comprehensive literature review. This review nicely summarized the key findings and future research direction related to the development of FTO inhibitors. The figure illustrations are also helpful to the readers. References are appropriately cited.
Response: We thank the reviewer for providing positive comments.

Comment 1 from Reviewer 2: As indicated by the title, this review aims to discuss the potential of FTO inhibitors in cancer treatment. To this end, the authors should provide more detailed explanations on how FTO is deregulated in human cancers and how FTO deregulation contributes to human carcinogenesis.
Response: We gratefully appreciate for these suggestions. We have added detailed explanation on the oncogenic role of FTO in several cancers in the section of “Biology of the FTO demethylase and its association with cancer” (Line 103-133). These changes have been highlighted in red color in the revision.

Comment 2 from Reviewer 2: Cancer is a heterogeneous disease. Up-regulation of FTO has been reported in some cancers, but on the other hand, FTO was down-regulated in other cancers. The applicability of FTO inhibitors in different cancer types should be discussed. In addition, intertumoral heterogeneity within the same type of cancer is also common. Is there any potential biomarker that can predict the treatment outcome of FTO inhibitors?
Response: Thank you for the insight comments, and we totally agree with the reviewer. Because of the heterogeneity of different cancer types and within the same cancer type, biomarker identification is vital for precise treatment and improved efficacy. However, no predictive biomarker for FTO inhibitors has been identified, to our best knowledge, which partly hinders the applicability of FTO inhibitors for precise treatment of cancers. Opposing expression level of FTO in different cancers was reported, indicating the context-specific role of FTO in different cancers, which might be the consequence of the diversity of modified RNA species (I. Barbieri and T. Kouzarides, Nat. Rev. Cancer, 2020, 20, 303-322). In order to further deliver this important viewpoint in our review, we have added more explanations for the cancer types that FTO is upregulated (Line 104-110) and down-regulated (Line 126-130). In addition, we have discussed the importance of biomarker identification for the development of FTO inhibitors (Line 692-696).

Comment 3 from Reviewer 2: The target specificity of FTO and other RNA demethylases should be discussed. FTO-specific probes are definitely valuable for dissecting the molecular pathway regulated by FTO. However, in terms of cancer therapeutic, would pan-RNA demethylase inhibitors have any advantage?
Response: We thank the reviewer for the valuable comments. We agree well with the reviewer that pan-RNA demethylase inhibitors would be a potential promising strategy for cancer treatment as it would lead to dramatically increased m6A level, while selective chemical probes for each demethylase are extremely valuable for exploring specific pathway regulated by FTO and ALKBH5, respectively. We added these discussions about this issue in Line 719-727.

Comment 4 from Reviewer 2: The anticancer effects of FTO inhibitors in animal models should be highlighted.
Response: Yes, we have highlighted the anticancer effects of FTO inhibitors in animal models in our revision.

Comment 5 from Reviewer 2: It will be good to have a small paragraph to summarize the current limitations in the field and future perspectives.
Response: Thanks for the helpful advice. We have summarized the current limitations such as lack of biomarker identification, less understood tumor biology, and few studies on FTO druggability. In addition, the future perspectives is included in the “Discussion and conclusion” section (Line 690-713).

26-Jul-2021

Dear Dr Yang:

Manuscript ID: CB-REV-04-2021-000075.R1
TITLE: Targeting the RNA demethylase FTO for cancer therapy

Thank you for submitting your revised manuscript to RSC Chemical Biology. After considering the changes you have made, I am pleased to accept your manuscript for publication in its current form. I have copied any final comments from the reviewer(s) below.

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With best wishes,

Professor Zaneta Nikolovska-Coleska
Associate Editor, RSC Chemical Biology

Reviewer 2

The authors have satisfactory addressed all my comments

Reviewer 1

The revised manuscript has answered most inquires raised by referees and may be acceptable for publication.