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Page 8 of 11 Tessari et al. J Cancer Metastasis Treat 2020;6:18 I http://dx.doi.org/10.20517/2394-4722.2020.32

Firstly, we have not fully elucidated the molecular role of RANBP9 is in the DDR. The nuclear accumulation
within hours after genotoxic stress suggests the participation of RANBP9 in the resolution of the
damage. Apart from being constitutively expressed in the CTLH E3 ligase complex, RANBP9 has also
[86]
been physically linked to the proteasome . Therefore, it is conceivable that it mediates the turnover of
proteins that are directly involved in the repair of DNA that need to be disposed of according to the tightly
concerted choreography of the DDR [87,88] .

With regards to the subnuclear localization of RANBP9 during the DDR, a question which remains is
whether RANBP9 is physically present at sites of damage. Novel tools such as the cell and mouse lines with
the endogenous RANBP9 tagged may be instrumental in answering this in-vivo question.

In addition, Tip60 modulates the acetylation of DNA following cellular damage [89,90] . Whether the absence
of RANBP9 results in differences in histone acetylation should be a major topic of investigation.

For future clinical management and stratification of patients, a thorough investigation on the outcomes
of treatment in the absence of RANBP9 should be conducted using cells containing different mutational
[91]
status of p53 . With regard to this, the p53 pathway is the main regulator of cell metabolism [92-94] .
Recently, RANBP9 has been shown to impinge on crucial metabolic nodes such as AMPK and MTOR
[53]
signaling including processeses such as autophagy . Therefore, the metabolic consequences as a result
of the absence of RANBP9 should be investigated to ascertain whether drugs targeting specific metabolic
pathways should be used in combination with DNA damaging agents.

In summary, RANBP9 is highly expressed in NSCLC, participating in critical signaling pathways. Therefore,
targeting this specific protein may significantly weaken the ability of tumor cells to survive and proliferate
when treated with DNA damaging or other types of drugs. Similar consideration may be made with other
malignancies in which RANBP9 has been found to be highly expressed.

DECLARATIONS
Authors’ contributions
Performed experiments: Tessari A, Soliman SHA, Orlacchio A, Capece M, Palmieri D
Elaborated data, prepared figures: Tessari A, Soliman SHA, Palmieri D
Read and edited the manuscript: Amann JM, Visone R, Carbone DP, Palmieri D
Conceived research, wrote manuscript, prepared figures: Tessari A, Palmieri D, Coppola V
All authors approved the manuscript.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported in part by funding provided by the Ohio State University Comprehensive Cancer
Center (P30 CA016058).

Conflicts of interest
The authors declare that they have no conflicts of interest.

Ethical approval and consent to participate
Not applicable.