Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

Round 1

Reviewer 1 Report

Hypoxia-inducible factors (HIFs) activate the transcription of genes that are involved in crucial aspects of cancer biology and inhibition of HIFs activity could be very efficient anti-cancer therapeutics. In this manuscript, the authors summarized the role and mechanisms of HIF in cancer progression and HIF associated cancer therapies. Overall, this is an interesting topic. My specific comments are listed below.

1.      Both figures ware adapted from Ziello’s work (Yale J Biol Med, 2007) which was published 16 years ago. I strongly suggest the authors should make new diagrams that include recent progress about HIF research. And in figure 2, “Translation of HIF1-α regulated enes into proteins” should be “Translation of HIF1-α regulated genes into proteins”.

2.      Considering there are lots of review papers that discussed HIF functions in cancers and HIF associated cancer therapies, to include the most recent progress is required for a meaningful review study. So, some recent studies should be discussed in this manuscript, such as “Science. 2018 Jul 20;361(6399):290-295. eLife. 2021; 10: e70412; Nat Commun. 2022 Jan 14;13(1):316”.

3.      As a review paper, it is highly recommended that the authors should combine their own related research work with other literatures to give some perspective comments.

4.      A HIF-2α inhibitor, Belzutifan (PT2977), was approved by FDA to treat patients with advanced kidney cancer. This is an important event in the field of therapeutic targeting of HIF-1 in cancers and should be mentioned in this study.

5.       In Table 1, the references should be listed in the table along with the corresponding HIF-1α inhibitors. And a new HIF-1 inhibitor, 32-134D ((J Clin Invest. 2022 May 2;132(9):e156774) should be included.

The quality of English language is good.

Author Response

Author Response File: Author Response.docx

Reviewer 2 Report

The review concerns the therapeutic targeting of HIF1 in cancer. In particular, the authors declare that the main role of HIF1 in the regulation of angiogenesis, cell proliferation, and glucose metabolism will be explored in depth and that emphasis will be given to the potential of HIF-targeted therapies in the disruption of cancer-related signal pathways. However, the review appears rather superficial and would need to be substantially improved to be published.

Some suggestions:

1.       The same concepts are often repeated throughout the text (for example the definition of hypoxia or angiogenesis, the fact that the HIF1 alpha subunit is oxygen-sensitive, and so on);

2.       In “HIF structure and physiology” only HIF1 alpha is described, but no informations about HIF2 and HIF3 alpha are included

3.       Other oxygen-independent mechanisms of HIF1alpha expression should be cited

4.       In my opinion, the role of HIF in the different types of cancer should be treated separately without subparagraph

5.       A column should be added to Table 1, containing the relevant bibliography. Furthermore, the name of all the inhibitors should be reported

6.       In the text, all spaces between the sentences must be eliminated

Author Response

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors revised their manuscript and provided relatively reasonable explanations for my questions. Some details were also added into this manuscript. The data in this study are integrated and more convincing. This manuscript should be able to bring the readers some understanding about the role of Hypoxia-Inducible Factor (HIF-1) in cancers. I have no more questions for the current version.

Author Response

Thank you for your approval of the revised manuscript

Reviewer 2 Report

The manuscript could be accepted in the current form

Author Response

Thank you for your approval of the revised manuscript