PONE-D-20-13714

LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production

PLOS ONE

Dear Dr. Xu,

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Chih-Pin Chuu, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Prostate cancer is a very common malignant tumor, and there are many cases with either recurrence after primary local therapy or with advanced stage at first diagnosis. First-line therapy in this situation is usually androgen deprivation. After some time, there is often development of a castration-resistant prostate cancer (CRPC), and treatment options at this stage are still limited, because knowledge about mechanisms driving CRPC is limited. There is published evidence that LPCAT1 is highly expressed in CRPC tissue, and that it is a prognostic biomarker in prostate cancer. Furthermore, various papers demonstrate an oncogenic function of PAF in different tumors.

The aim of this study was to analyze the role of LPCAT1 and PAF in CRPC in further detail. The authors performed different cell culture experiments on two prostate cancer cell lines, and also some in vivo experiments on nude mice. They found that LPCAT1 can enhance tumor cell migration and invasion in a PAF-dependent manner. In contrast, cell proliferation was independent of PAF, and instead associated with androgen-dependent nuclear localization of LPCAT1. In the nucleus, LPCAT1 can drive palmitoylation of histone H4, leading to increased mRNA synthesis. Furthermore, elevated LPCAT1 levels reduced the sensitivity of prostate cancer cells to paclitaxel, which is a common drug in CRPC.

The topic of this study has high relevance in the field of advanced prostate cancer, because only a few mechanisms driving CRPC progression are known so far, and new potential therapy targets are urgently needed. Therapeutic modulation of LPCAT1, PAF or epigenetic modifications like histone palmitoylation might be novel approaches in the future. The strength of this study is the comprehensive experimental approach including many different cell culture experiments (measurement of cell cycle, mRNA level, proliferation, migration, invasion, apoptosis, gene transfection and silencing, Western Blot) and in vivo experiments with tumor xenografts in nude mice. The experiments are well planned, and the results give new insights in cell biology mechanisms that were previously not known in CRPC. The presentation of the results in the text and in the figures is concise and clear, the discussion is concludent.

Minor revision:

In 3.4. (Results) a histone H4 S47A mutation was transfected into the tumor cells, resulting in a decreased LPCAT1-dependent mRNA synthesis and reduced RNAP II activation (Figure 4F). It is concluded that this indicates a role for O-palmitoylation of histone H4. The authors should explain in some more detail the effect of this mutation and the conclusion of O-palmitoylation as a potential mechanism in CRPC biology.

Summary:

This well conducted study gives new insight in cell biology mechanisms that play are role in CRPC. LPCAT1 might be a target for therapeutic approaches in the future (e.g., modulation of LPCAT1 to increase sensitivity against paclitaxel), albeit this basic research results can be only the very first step on the way to clinical application.

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Reviewer #1: No

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LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production

PONE-D-20-13714R1

Dear Dr. Xu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Chih-Pin Chuu, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No