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Tessari et al. J Cancer Metastasis Treat 2020;6:18 I http://dx.doi.org/10.20517/2394-4722.2020.32 Page 5 of 11

pursuit of biomarkers with “BRCAness-like” status in malignancies other than breast and ovarian cancer,
including that of NSCLC [59,60] .

Herein, we show that RANBP9 KO NSCLC cells have increased sensitivity to ATR inhibitors while not
having the same response to ATM inhibitors [Figure 2]. In essence, we hypothesize that RANBP9 levels
of expression may be predictive of patient response to specific DNA damaging agents in the clinics.
[50]
Nevertheless, a prospective study will be necessary to prove this hypothesis .
[50]
As a whole, RANBP9 is highly expressed in NSCLC compared to normal adjacent tissue . However, we
have found that the levels of protein expression may not necessarily correlate with the cellular transcription
levels. We found this lack of correlation in commonly used NSCLC cell lines as well as in a limited number
[50]
of freshly extracted NSCLC patient samples . This observation needs to be further substantiated and
confirmed in other studies. However, it is not unusual for proteins which are part of macromolecular
complexes to modulate other proteins’ stability [61,62] . In addition, RANBP9 is involved in the response
to stress and it is conceivable that protein levels are not always regulated by mRNA expression [61,62] . If
confirmed, the lack of correlation between RANBP9 protein and mRNA amounts will have profound
implications. In fact, it indicates that only the study of protein levels can provide a reliable assessment of
the expression of RANBP9.

Taken together, RANBP9 is highly expressed in NSCLC cells as compared to normal lung tissue [50,51] .
However, this does not preclude the untested possibility that RANBP9 may possess a tumor suppressive
function during the initial phases of NSCLC tumorigenesis due to its role in promoting genomic stability.
This hypothesis needs to be tested in relevant preclinical models. However, it is conceivable that RANBP9
opposes initiation but may later becomes advantageous for tumor progression, which is similar to TGF-b
related signaling pathways [63,64] .

ONGOING INVESTIGATIONS
Studying the role of RANBP9 in the context of cellular response to stress and DNA damage is a major focus
of our group. We are currently exploring three specific aspects of RANBP9 biology in response to genotoxic
[65]
stress. The first is the close association of RANBP9 with the “guardian of the genome” known as p53 . The
second relates to the mechanisms underlying the augmented sensitivity to DNA damaging drugs caused
by the lack of RANBP9. Finally, we also consider the potential partial functional redundancy of RANBP10.
Due to the presence of high homology, this second Scorpin (Spry-COntaining Ran binding ProteIN) and
paralog cannot be ignored, and it is likely a major confounding factor in establishing the importance of
RANBP9 [66,67] .

RANBP9 and p53 in the DDR
As a consequence of impairment of ATM signaling in the absence of RANBP9, we have reported that
phosphorylation of p53 on Serine 15 is severely compromised, affecting the total expression of p53 as
shown in Figure 3 [50,56] . The relationship between RANBP9 with p53 is likely more complex than anticipated
and worthwhile to be further investigated. Although an interaction has been previously described between
RANBP9 and a specific isoform of p73 by co-IP and colocalization, three groups including ourselves
have failed to demonstrate a physical interaction between RANBP9 and p53 by co-IP [42,68] (and Coppola,
unpublished results). Nevertheless, a high throughput study reported a co-IP between RANBP9 and the
[69]
p53 R273H mutant that needs to be further validated . In summary, it appears that the effects of the
absence of RANBP9 on p53 total and phosphorylation levels upon DNA damage are indirect. How the
absence of RANBP9 negatively affects ATM-kinase remains to be clarified, but the blunted ATM activity
could potentially explain the decrease in p53 levels. On the other hand, an impaired ATM signaling may
be only one of the possible mechanisms through which RANBP9 affects p53 abundance and activity.