HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

As explanation:

The manuscript starts with an   introduction about heat-shock proteins, including a brief description of the   HSP90 family. It continues with the role of HSP90 in cancer hallmarks,   describing the hallmark ‘metabolism’ in more detail. In principle the lines   182-205 are not relevant for the further content, ‘metabolism and   epigenetic’, of the manuscript.

During the next part, the   authors give some examples of HSP90 clients regulating metabolism. This part   makes sense since it describes Hsp90 clients which are able to regulate   metabolism.

The fourth chapter is again   very detailed and partly redundant, since it often repeats definitions and   explanations of earlier parts, e.g. line 352-380 could be shortened.

In principle, the following   passages of this chapter describe now the connection between HSP90 and   epigenetic which makes sense.

But the last chapter, chapter   5, loses now completely the connection to the HSP90 system. It just describes   all possible interplays between epigenetic and metabolism, very detailed, but   without any clear explanations how HSP90 is involved. Within this complete   chapter 5, I could not find any ‘HSP90’ wording anymore. That means I have to   scroll back several times to find the Hsp90 clients which serve as bridge   between epigenetic and metabolism. I would highly suggest to rewrite, or   better somehow to include the chapter 5 into earlier chapters, to better   explain the interplay/crosstalks between HSP90, epigenetic and metabolism. In   this present form, chapter 5 feels like an own review, without access to   HSP90.

Some minor concerns regarding   chapter 1 - 4:

- Chapter 2 should explain the   difference between the ‘normal’ and the ‘tumoral’ HSP90 system. The function   of HSP90 is completely subverted during tumorigenesis, from a system which   normally protects cells from aberrant proteins, to a system which now   protects truncated, mutated and aberrant folded proteins. This is a major   point to understand the nature of the tumoral HSP90 system to drive cancer. Further,   tumoral HSP90 has now a higher affinity to their clients and built up the   so-called super-chaperone complexes including HSP70, HSP40 and lots of   co-chaperones. Such complexes need now much higher energy/ATP to fulfill   protein protection/stabilization.

- It could be interesting to   understand how nuclear HSP90 comes into the nucleus. Does it need   transporters, etc.? HSP90 is known to protect proteins during the transport   trough the cytosol to the nucleus, e.g. hormone receptors, but does not enter   the nucleus. Normally, HSP90 complexes dissociate if a client is stabilized   by their ligand. If this review focusses on epigenetic, the nuclear   localization needs to be further investigated.

- It is known that the HSP90   activity is regulated by modifications such as acetylation. This manuscript   mentioned HDAC regarding histone modification, of course. But what is with   HSP90 activity?  

- line 832: Ganetetispib

- line 853: the   literature/citation is missing  

The description of cancer   hallmarks was shortened, but kept to a minimum to help the understanding of   subsequent paragraphs (lines 198-215).

According to reviewer suggestion,   chapter 4 was shortened removing some   redundant sentences (lines 385-406). 

We agree with the Reviewer that  chapter 5 loses the connection with HSP90. Thus, chapter 5 was amended to   highlight the interplay between HSP90, metabolism and epigenetics. More   specifically, we mentioned HSP90 client proteins involved in metabolic   changes and potentially responsible for epigenetic modifications. However, it   is important to note, that this is a field of intense investigation and that   several issues are still unknown (Chapter 5, lines 561-563; 593; 628-629;   638-639; 688; 690-692; 757-758; 792; 823-824).

The concept that molecular   chaperones play a different role in transformed versus non-transformed cells   has been better specified. We underlined that cancer cells upregulate   molecular chaperones to fold aberrant and mutated proteins and that they form   heteroprotein complexes with client proteins and co-chaperones (Chapter 2,   lines 123-127).

There is very limited information   on the mechanism used by HSP90 to translocate to the nucleus. However,   Chromatin IP-seq experiments showed that HSP90 directly interacts with   chromatin. Furthermore, it has been proposed that HSP90 phosphorylation is a   prerequisite for its nuclear translocation. The relevance of this mechanism   in mammalian cells is still under investigation. These data were specified in   the Review (lines 459-463).

 As suggested by the Reviewer, the   effect of post-translational modifications on HSP90 chaperones is a relevant   issue. Thus, we reported some evidences about acetylation-dependent HSP90s   activity. However, it is important to note that the effect of HSP90   deacetylation and/or acetylation on metabolism reprogramming and epigenetics   is still unknown (lines 901-920; 926-931; 934-936).

The name of the inhibitor was   corrected (line 948).

The reference was added (line 963).

The authors have presented a comprehensive review of the connections   between HSP90 molecular chaperones and epigenetic signals in cancer. Overall,   the manuscript is very well written and addresses the many points at which these   seemingly unconnected topics overlap. This reviewer finds no significant   complaints with the manuscript aside from the occasional stylistic concern   (For example, Lines 400-402 are represented as a single paragraph-- a single   sentence does not constitute a paragraph). Regardless, this does not diminish   the quality of this review.

Many tanks to the Reviewer for its favourable   evaluation. Stylistic concerns were addressed.