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Thank you for attending to these issues. I am happy to recommend acceptance now.
[# PeerJ Staff Note - this decision was reviewed and approved by Sonia Oliveira, a PeerJ Section Editor covering this Section #]
Although both reviewers agree the manuscript is much improved, both (and I) believe that further work on the structure and clarification is needed. The reviewers have been quite clear in what they think is required. Please take these comments on board and revise again accordingly.
The English is mostly clear but there is some ambiguity in some of the sections. The authors need to thoroughly check the article for ambiguity. The article is generally well referenced. The structure is professional. Review article so raw data not relevant. Review is broad and cross disciplinary. I am not aware of recent reviews on the topic. Introduction is adequate.
No comment
I feel that some of the arguments need to be developed.
The article is improved from the first time I reviewed it but I still feel that it reads a bit like a list and that arguments are not fully developed as to how different PTM's influence prostate cancer. The section on lipidisation did not cover post translational lipid modifications in my opinion. There are a few minor things that I spotted that I feel need addressing.
Line 21 First sentence of abstract needs changing. Through the covalent attachment of functional groups or small proteins, proteolytic cleavage for regulation or degradation of proteins….
Line 25 Also do not know what the phrase ‘nearly normal biological cell function’ is meant to mean
Line 45 sentence does not make sense. States that IL-6 phosphorylates PD-L1. IL-6 is not a kinase. Also states that activation of JAK, catalyses glycosylation of PD-L1. JAK is a kinase so how can it catalyse glycosylation?
Lines 51-65 Felt the examples were a bit random. Maybe stick to examples relevant to cancer.
Line 81. I would remove ‘Therefore’
Line 109 I assumem you mean FGFR and not FGF which is not a kinase
Line 110 are cdk’s tyrosine kinases?? I thought they were S/T kinases. I feel tis sentence is very long and needs to be split
Line 114. Targetting rather than targeted
Line 165. Do you mean easy progression?
Line 213 It is not clear to me what the relationship between GDF15 and EGFR is.
Line 218 How has FUT8 been implicated in tumour metastasis?
Line 225 core fucosylated what? Core fucosylated glycoproteins?
Line 287 Do not start a new section with similarly. Similarly to what?
P301 Function functionally needs changing
Line 423-459. This section does not cover post translational lipid modifications of proteins in any detail. Seems to be about lipid metabolism. Don’t really see the relevance to the topic.
I thank the authors for taking on board the reviewer comments and revising their manuscript accordingly, including the addition of new explanatory material.
There are a few points that remain to be addressed.
1. Although the authors have now included a nice introduction to prostate cancer, I still feel the introduction is somewhat overwhelming in terms of signalling detail. Lines 48-68 in particular are very dense. It would be better if the introduction was structured in such a way that the different classes of PTM are introduced with some basic principles, and illustrated with ‘big picture’ examples that are described with context and sufficient explanation to understand them. It's not really necessary in this broad introduction to report specific molecular modifications and mechanisms.
2. I request again that the authors use the term “lipidation” instead of “lipidization”.
The post-translational modification of proteins with lipids is usually performed by acyl transferase enzymes in a process termed lipidation.
From a review of the literature, lipidization appears to be used more commonly in the field to describe the chemical modification of eg. peptides or drugs with lipid moieties.
To illustrate my point, the search “lipidization AND acyl transferase” in PubMed yields 3 hits, while “lipidation AND acetyl transferase” yields 23,655 hits.
3. In the Figure 3 legend, “Activation of AMPK can inhibit these pathways through direct phosphorylation of key lipoblasts and key kinases (such as ACC or TSC1 / TSC2) or through regulation of SREBP1c transcription. The black and red arrows indicate activation and repression, respectively.”
I’m not sure what phosphorylation of ‘key lipoblasts’ refers to, and ACC, TSC1/2 are not kinases. Finally, there are only black and blue arrows, not red.
4. There are still a lot of spacing errors between the in-text citations and the main text.
NA
NA
None.
As you will see, both reviewers are largely positive that this review makes an important contribution to the field and are supporting publication, subject to some issues being addressed. These are clearly explained in their reviews, and one of the reviewers has also edited your PDF, which I enclose here.
I therefore have indicated a 'major revisions' which reflect that there is quite bit of editing and re-arranging/re-writing to do. Please clearly explain in a cover letter how your revisions address each point.
**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
The review is mostly written in reasonably clear professional English although there are errors that need addressing. The introduction needs some substantial additions in my opinion. It is a little too vague and focusses only on the generics of PTM’s. Maybe provide some specific, well established, examples of how dysregulation of PTM result/contribute to disease such as cancer. I also feel that there needs to be some introduction of prostate cancer specifically and molecular features of prostate cancers. Current therapies could be briefly introduced. I am not an expert on prostate cancer but believe androgen deprivation therapy is a common therapeutic option. This may be inferred in some of the sections but the importance not emphasised. Androgen receptors feature quite a lot in the review so to justify importance they need to be introduced. A good informative introduction is necessary to put the content of the review into context. Quite a lot of the content throughout the review needs requires more explanation in my opinion. For example ‘The COP9 complex subunit (COPS3) is highly expressed…. Is mentioned but not explained. I looked it up and the COPS3 subunit of the signalosome is a protein kinase. There are numerous places where I feel further explanation is necessary to make the review clearer.
The review is well referenced. The review could be better organised in my opinion. Within each section I feel that the subsections could be more clearly defined, possibly with further subheadings. Rationale for why points are relevant to the topic could be made clearer in places. It was not always obvious how observations made in the same paragraph were linked to one another.
Many of the arguments provided need to be developed further in my opinion. The sections read a little too much like a list of observations from articles rather than well-reasoned, interconnected arguments justifying inclusion in the review.
The conclusions and future perspectives were, like the introduction, a bit too vague. Sentences such as ‘In addition the post-translational modification of proteins can provide new drug targets and screening methods for drug discovery’ are too generic and not very informative. Sentences such as Kinase inhibitors, methyltransferase inhibitors, …..have achieved remarkable success in clinical use need to be justified and referenced. PROTACs mentioned a couple of times but no specific suggestions as to how they could be developed and used are provided.
I have made comments on part of the review to indicate the types of content I feel need addressing. I did not make comments on the whole document.
This review attempts to summarise the state-of-the-art of post translational modifications (PTMs) of proteins in prostate cancer. This is a vast undertaking for a relatively short article format. A survey of the secondary literature in this field reveals that most reviews tend to focus on one or two facets of signalling in prostate cancer rather than all PTMs.
The authors state that the review is aimed at a broad audience, but I argue that a non-specialist would find this manuscript overwhelming. Fundamentally, this review requires a major overhaul involving a narrowing of the scope and addressing the following issues:
1) Due to the review being written from the perspective of the various PTMs, the introduction and sub-sections do not properly introduce prostate cancer, which would help provide context for a general audience. There should be an initial sub-section of the review that summarises the key features of prostate cancer (and the need for better and personalised therapies) and sets the scene for the sections that follow.
2) In trying to cover the breadth and depth of the field, large sections of the text are effectively lists of signalling events, which are impenetrable without more detailed explanation. For example, lines 72-89 in the protein phosphorylation sub-section cover multiple unrelated phenomena involving seven (!) kinases with very little detail or explanation.
3) The figures depicting the selected signalling pathways are too generic and hence not very helpful. There is a disconnect between the simple pathways presented and the incredibly complex signalling described in the text of the review. The figures should be bespoke for signalling pathways in prostate cancer and properly support the reader’s understanding of the mechanisms described. The legends should be more explanatory.
4) Presumably due to the lack of space, there is often no mention of the system used in the research findings described (eg. cell line, animal model, patient treatment/trial), which makes it difficult to evaluate the importance and validity of the data. At times, the authors appear to lend equal weight to all the research described.
5) The text requires proofreading for grammar and spelling, but there are also other errors. Some examples include:
- The definition of ‘acetylation’ in Table 1 is stated as the chemical definition rather than the biochemical definition
- The second column title of Table 1 is ‘Machine added’ but I think should probably be ‘Mechanism’
- In places the terminology is wrong (eg. ‘lipidization’ or ’lipinization’ instead of lipidation).
- Many abbreviations have not been defined (eg. BPH, CRC, LacdiNAc, diantennacan?).
- The titles for Figures 3 and 4 have been switched by mistake.
As stated in the methodology, the authors have reviewed all the literature found in database searches that cover the various PTMs and prostate cancer. Overall, the review is well-referenced and it is interesting that they have included less well understood modifications, such as lactation, succinylation etc.
The supplementary tables present an impressive overview of the author’s review of the field, but also demonstrate that the scope of the review is too ambitious.
As already mentioned, the introduction is too ambitious in its aims and there is too much content in the main text of the review to develop a clear and coherent narrative. However, the discussion section pulls together some interesting themes to outline putative therapeutic approaches.
Perhaps an appropriate niche for this review would be to inform on the less well understood PTMs and outline emerging themes in the research and how understanding these mechanisms / pathways might lead to novel therapies in prostate cancer.
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