Regulation of Keratin Chemical Modifications: Potential Molecular Mechanisms in Proliferative Diseases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review highlights the essential role of keratins in maintaining epithelial integrity and their involvement in proliferative disorders such as cancer and fibrosis. It emphasizes how post-translational modifications, including phosphorylation, acetylation, and methylation, modulate keratin structure and function, thereby influencing key signaling pathways that drive disease progression. By systematically examining keratin classification, physiological roles, and the molecular mechanisms linking keratin modifications to fibrosis and cancer, the review addresses important gaps in current knowledge. The authors also discuss emerging therapeutic strategies targeting keratin expression or modification, underscoring the potential of keratin-focused approaches for treating fibrosis and cancer.

• I suggest that the authors expand the background section by including an overview of the keratin gene family. Specifically, please indicate the total number of known functional keratin genes and clearly distinguish which belong to type I and which belong to type II. Presenting this information in a concise table format would greatly improve clarity. In addition, please briefly summarize what is currently known about the biological function of each gene (or major subgroups) and indicate whether all keratin genes have been equally well studied or if knowledge remains limited for certain members of the family.

 

• In line 132, the authors state that “keratins serve critical roles in non-classical physiological processes such as immunological modulation, metabolic regulation, signaling, and antimicrobial activity.” While immunological modulation, metabolic regulation, and signaling are discussed later in the manuscript, the role of keratins in antimicrobial activity is not addressed. The authors should either include a brief discussion of this function with appropriate references or revise the statement to accurately reflect the content presented.

 

 

• Under the heading “The role of keratin modifications in proliferative diseases,” the authors focus exclusively on liver fibrosis, liver cancer, and colorectal cancer. This presentation may give the impression that the role of keratins in cancer is limited to these conditions, which is not the case. Numerous studies have reported important roles for different keratins in other malignancies, including but not limited to lung, breast, and gastrointestinal cancers. If the authors intend to restrict this section primarily to liver-related diseases, the title should be revised accordingly to reflect this narrower scope. Otherwise, the authors should expand this section to incorporate a broader discussion of keratin involvement across multiple cancer types.

 

• Are there additional roles for keratins in other proliferative diseases such as Psoriasis, beyond cancer and fibrosis, as implied by the title of this review? If the scope of the review is limited primarily to cancer and fibrosis, the title should be revised accordingly to reflect this focus. Alternatively, the authors should expand the discussion to include keratin functions in other proliferative disorders.

Author Response

1.

• I suggest that the authors expand the background section by including an overview of the keratin gene family. Specifically, please indicate the total number of known functional keratin genes and clearly distinguish which belong to type I and which belong to type II. Presenting this information in a concise table format would greatly improve clarity. In addition, please briefly summarize what is currently known about the biological function of each gene (or major subgroups) and indicate whether all keratin genes have been equally well studied or if knowledge remains limited for certain members of the family.
• response:The description of the keratin gene family has been added to the article and has been organized into a table.
• 2.
• In line 132, the authors state that “keratins serve critical roles in non-classical physiological processes such as immunological modulation, metabolic regulation, signaling, and antimicrobial activity.” While immunological modulation, metabolic regulation, and signaling are discussed later in the manuscript, the role of keratins in antimicrobial activity is not addressed. The authors should either include a brief discussion of this function with appropriate references or revise the statement to accurately reflect the content presented.
• response: The research on antibacterial activity is very limited. The term "antibacterial activity" has been revised and deleted in the original text.
• 3
• Under the heading “The role of keratin modifications in proliferative diseases,” the authors focus exclusively on liver fibrosis, liver cancer, and colorectal cancer. This presentation may give the impression that the role of keratins in cancer is limited to these conditions, which is not the case. Numerous studies have reported important roles for different keratins in other malignancies, including but not limited to lung, breast, and gastrointestinal cancers. If the authors intend to restrict this section primarily to liver-related diseases, the title should be revised accordingly to reflect this narrower scope. Otherwise, the authors should expand this section to incorporate a broader discussion of keratin involvement across multiple cancer types.
• response: In this section, we’d like to focus on presenting research related to the chemical modifications of keratin, rather than delving into how keratin expression functions in diseases.
• 4
• Are there additional roles for keratins in other proliferative diseases such as Psoriasis, beyond cancer and fibrosis, as implied by the title of this review? If the scope of the review is limited primarily to cancer and fibrosis, the title should be revised accordingly to reflect this focus. Alternatively, the authors should expand the discussion to include keratin functions in other proliferative disorders.
• response: Although research on keratin chemical modifications in proliferative diseases remains limited, psoriasis has been included in some studies. However, keratin modifications in other proliferative disorders have yet to be thoroughly investigated.

Reviewer 2 Report

Comments and Suggestions for Authors

Only epithelial cells, the skin, and its appendages contain keratin, a member of the intermediate filament protein family (54 species). Mutations in keratin cause a variety of skin conditions, including hyperkeratosis, ichthyosis, and porokeratosis, as well as the pathophysiology of cancer. Cell polarity, linkage to the basement membrane, material transport, cell migration, and apoptosis are all provided by keratins, which are linked to desmosomes (intercellular adhesion) and hemidesmosomes (cell adherence to the matrix).Certain keratins were found to be overexpressed, such as in breast cancer (K17), and they may play a part in the growth and spread of malignancies (KRT7, K8|18). Though some malignancies are employed as diagnostic markers, there is no clear connection between keratin chemical alteration and tumors. Phosphorylation, methylation, and other posttranslational changes are important in this. It is necessary to close this gap since, despite the wealth of research in this field, there is still disagreement over the part post-translational modifications of keratin play in the pathophysiology of illnesses. The authors of this review concentrate on providing an overview of the information that is currently available on the connection between cancer and post-translational changes of keratin.

The review is organized logically and gives a general overview of keratin, including its structure and functions, its role in immune response mechanisms, its metabolism, the interpretation of its significance for epithelial cells, its involvement in pathological processes, such as fibrosis and tumors, and the significance of comprehending the post-translational modifications of keratin for these processes. As a result, this review covers a broad spectrum of current keratin knowledge, which is quite pertinent.

The writers employed 160 primary sources, the majority of which are no older than five years, to write this review. The remaining references are also pertinent. The authors attempt to examine and synthesize the acquired data on keratin and post-translational changes in the Introduction section, citing the lack of systematic organization as justification for the need for this analysis. The most recent review of keratins and cancers was released in 2022. It looks at how colonic mucosal keratins maintain crypt epithelial homeostasis, control metabolism, and relate to each other.

The writers employed 160 primary sources, the majority of which are no older than five years, to write this review. The remaining references are also pertinent. The authors attempt to examine and synthesize the acquired data on keratin and post-translational changes in the Introduction section, citing the lack of systematic organization as justification for the need for this analysis. The most recent review of keratins and cancers was released in 2022. It looks at how colonic mucosal keratins maintain crypt epithelial homeostasis, control metabolism, and relate to each other (Evans CA, Corfe BM. Colorectal keratins: Integrating nutrition, metabolism and colorectal health. Semin Cell Dev Biol. 2022 Aug;128:103-111. doi: 10.1016/j.semcdb.2021.08.010. Epub 2021 Sep 1. PMID: 34481710.). The review writers' conclusion is supported by the research findings of other authors, which were examined throughout the creation of this article and do not raise any questions. The review's statistics and charts make the work information easier to understand.

Simultaneously, the following remarks and recommendations are made for the review:
1. Italicize the Latin words (lines 70, 170, 171, 216, 432).

2. Table 1 should be placed on page 3, not page 6, right after it is mentioned in the text. To make the table easier to read, the writers may choose to provide references to primary sources.
3. Explain the final letter of the acronym hnRNPK (line 129). A class of RNA-binding proteins that are strongly associated with the biological functions of mRNA is indicated by the presence of an extra letter. The common shorthand for all types is hnRNP. Why was hnRNPK selected?
4. Line 159: Make it clear if the symbol is a comma or a period at the end of a phrase.
5. There is an additional space between the text and the table on line 165.
6. You use a lot of acronyms in the post without providing an explanation when they are first stated, which makes it challenging for non-experts to comprehend the material. It would be better to give an explanation right after the first mention, even though you do so near the end of the piece.
7. The explanation of the previously described abbreviation does not need to be repeated on line 262.

Author Response

1. Italicize the Latin words (lines 70, 170, 171, 216, 432).

response: All revisions have been completed.

• 2. Table 1 should be placed on page 3, not page 6, right after it is mentioned in the text. To make the table easier to read, the writers may choose to provide references to primary sources.
• response: Agreed. The form has been placed in the recommended location.
• 3. Explain the final letter of the acronym hnRNPK (line 129). A class of RNA-binding proteins that are strongly associated with the biological functions of mRNA is indicated by the presence of an extra letter. The common shorthand for all types is hnRNP. Why was hnRNPK selected?
• response: The hnRNP family includes multiple isoforms, such as hnRNP A1, A2, K and B1. The specific functions of each isoform in RNA metabolism may vary. In this section, we intend to focus on their roles in immune regulation, and in particular, hnRNP K is known to regulate the expression of chemokines during immune-inflammatory responses.
• 4. Line 159: Make it clear if the symbol is a comma or a period at the end of a phrase.
• response: It has been revised to a comma.
• 5. There is an additional space between the text and the table on line 165.
• response: The table has been revised and placed in the recommended position.
• 6. You use a lot of acronyms in the post without providing an explanation when they are first stated, which makes it challenging for non-experts to comprehend the material. It would be better to give an explanation right after the first mention, even though you do so near the end of the piece.
• response: The text has been revised and an explanation for the first occurrence of the abbreviation has been added.
• 7. The explanation of the previously described abbreviation does not need to be repeated on line 262.
• response: modified