3.5 5.

Review

Splicing Variants, Protein-

Protein Interactions, and Drug
Targeting in Hutchinson-
Gilford Progeria Syndrome
and Small Cell Lung Cancer

Bae-Hoon Kim, Tae-Gyun Woo, So-Mi Kang, Soyoung Park and Bum-Joon Park

Special Issue
Alternative Splicing in Human Physiology and Disease
Edited by
Dr. Christos K. Kontos and Dr. Pinelopi I. Artemaki

https://doi.org/10.3390/genes13020165
G C A T
T A C G
G C A T
genes
Review
Splicing Variants, Protein-Protein Interactions, and Drug
Targeting in Hutchinson-Gilford Progeria Syndrome and Small
Cell Lung Cancer
Bae-Hoon Kim 1 , Tae-Gyun Woo 1 , So-Mi Kang 2 , Soyoung Park 2 and Bum-Joon Park 1,2, *

1 Rare Disease R&D Center, PRG S&T Co., Ltd., Busan 46241, Korea; [email protected] (B.-H.K.);
[email protected] (T.-G.W.)
2 Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46274, Korea;
[email protected] (S.-M.K.); [email protected] (S.P.)
* Correspondence: [email protected]

Abstract: Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode
protein variants (isoforms) that give one gene several functions or properties. This process provides
one of the major sources of use for understanding the proteomic diversity of multicellular organisms.
In combination with post-translational modifications, it contributes to generating a variety of protein–
protein interactions (PPIs) that are essential to cellular homeostasis or proteostasis. However, cells
exposed to many kinds of stresses (aging, genetic changes, carcinogens, etc.) sometimes derive cancer
or disease onset from aberrant PPIs caused by DNA mutations. In this review, we summarize how
splicing variants may form a neomorphic protein complex and cause diseases such as Hutchinson-



Gilford progeria syndrome (HGPS) and small cell lung cancer (SCLC), and we discuss how protein–


protein interfaces obtained from the variants may represent efficient therapeutic target sites to treat
Citation: Kim, B.-H.; Woo, T.-G.;
HGPS and SCLC.
Kang, S.-M.; Park, S.; Park, B.-J.
Splicing Variants, Protein-Protein
Interactions, and Drug Targeting in Keywords: Hutchinson-Gilford progeria syndrome (HGPS); small cell lung cancer (SCLC); alternative
Hutchinson-Gilford Progeria splicing (AS); Progerin; DX2; protein-protein interactions (PPIs)
Syndrome and Small Cell Lung
Cancer. Genes 2022, 13, 165.
https://doi.org/10.3390/
genes13020165 1. Introduction
Academic Editors: Christos Around 44 years ago, Joseph Sambrook discovered the exon and intron in a gene
K. Kontos and Pinelopi I. Artemaki from an adenovirus, and Walter Gilbert suggested that different exon fusions in a gene
might be spliced together to make different mRNA isoforms [1,2]. As a result of scientists’
Received: 11 December 2021
efforts (the Human Genome Project) to create a global view of genomes, 20 years ago,
Accepted: 17 January 2022
scientists have calculated that an average human protein-coding gene has 8.8 exons, with
Published: 18 January 2022
an average of 145 nt. The intron length and the lengths of the 5′ and 3′ UTR are, on average
Publisher’s Note: MDPI stays neutral 3365 nt, 770 nt, and 300 nt, respectively [3]. Most protein-coding genes have introns that
with regard to jurisdictional claims in are degraded in the nucleus by the RNA splicing machinery. Exon usage is very often
published maps and institutional affil- alternative. The cell decides to get rid of introns from the pre-mRNA or include exon parts
iations. in the mature mRNA [4]. There are around 20,000 human gene-encoding proteins and
around 150,000 isoforms from RNA transcripts. Consequently, in general, each human
gene has about seven RNA isoforms. Recently, it was reported that over 30% of tissue-
dependent transcriptional variations are covered by local splicing variations, which are
Copyright: © 2022 by the authors.
described as a split in a splice graph into or from a single exon [5]. The resulting differences
Licensee MDPI, Basel, Switzerland.
among the mature mRNA isoforms produced by alternative splicing (AS) mean they can
This article is an open access article
encode different protein products, or affect the localization, stability, and translation of
distributed under the terms and
conditions of the Creative Commons
mRNA. When we consider that the high level of complexity in the human genome may
Attribution (CC BY) license (https://
be illustrated by the variability of each gene with AS, it is natural to think of the fine-
creativecommons.org/licenses/by/ tuning control of these as necessary and flexibility as risky. Considering the importance
4.0/). of RNA splicing for protein diversity and keeping the function of the organism, it is clear

Genes 2022, 13, 165. https://doi.org/10.3390/genes13020165 https://www.mdpi.com/journal/genes

Genes 2022, 13, 165 2 of 11

that disrupting normal splicing patterns can cause gene dysregulation and disease. For
example, autosomal dominant forms with mutations in the splicing core factors can cause
retinitis pigmentosa and Cerebro-Costo-Mandibular Syndrome [6–10], although there are
few reports of mutations in core splicing elements that result in human diseases. This is
likely because disruptions of basic factors in the splicing apparatus are normally more
fatal compared to mutations deriving from aberrant splicing of each gene. [11]. Besides
splicing core factors, many human diseases linked to defective splicing have been reported.
Aberrant splicing could be caused by mutations disturbing either trans-acting regulatory
genes (proteins) or cis-acting regulatory sequences, with the latter more frequently recorded.
It was recently reported that AS affects more than 85% of human protein-coding genes
for cells and increases their use of genetic information [12]. Protein parts are encoded by
approximately 75% alternative exons [13], and the alternate use of exons permits multiple
proteins to be made from one gene, which intensifies the coding potential of the genome.
It is suggested that most alternative exons encode coiled or loop regions on the protein
surface, meaning AS can affect the functional interface formation of many proteins [14].
Alternative splicing generates protein isoforms with various biological properties, which
can significantly affect protein–protein interaction (PPI), subcellular localization, or enzy-
matic ability [15]. This means that each cell might have evolved to increase the number
of protein pools to respond more efficiently to harmful stress conditions brought by AS.
PPIs are the main biochemical mechanisms of cellular life and are frequently disturbed in
disease condition. We predict that the numbers of protein interactions (an interactome)
in humans may add up to between 130,000 and 600,000 [16,17] (the number has been
increasing overtime). Protein interactions in functional multi-protein complexes that have
roles in basic processes such as protein transport, making an RNA copy of a gene sequence
(transcription), producing proteins from mRNA (translation), interaction/communication
between cells, protein modification, signaling cascades, and functional holoenzyme can
be explained by the PPIs. It is not surprising that when the homeostatic condition of
an organism or a single cell is interrupted (as a result of several stresses or in a disease
condition), the normal patterns of PPIs can be disturbed. Furthermore, aberrant PPIs from
splice variants, which are produced from mutations of a single gene in cis, could be the
causes of cancerous or disease-onset cells such as those of Hutchinson-Gilford progeria
syndrome (HGPS) and Small Cell Lung Cancer (SCLC) [18,19] (Figures 1 and 2).

Figure 1. Progerinin (SLC-D011) can ameliorate the nucleus deformation. Progerin is produced by
alternative splicing after mutation of LMNA gene. It interacts with Lamin A and generates strong
heterodimers. These induce the deformation of the nucleus. Progerinin (SLC-D011) can specifically
bind to Progerin and mediate it to the degradation.
Genes 2022, 13, 165 3 of 11

Figure 2. SLCB050 inhibitor can block the interaction between DX2 and P14/ARF. AIMP2-DX2
is produced by alternative splicing under oncogenic stress condition. It interacts with P14/ARF
and inhibits cell death and senescence. Small chemical SLCB050 can specifically bind to DX2 and
dissociate P14/ARF from DX2. It induces cell death or senescence dependent on P14/ARF and may
contribute to blocking lung cancer progression.

In this review, using the examples of human diseases HGPS and SCLC, we will
introduce their etiology by abnormal alternative splicing and present the aberrant protein
complexes that lead to the diseases. We will focus on the interfaces of protein–protein
interaction to select therapeutic targets. In this article, we will highlight the proven or
possible PPI interfaces that may cause disease onset and that could represent potential
therapeutic targets in SCLC and HGPS.

2. HGPS and Present Therapeutic Agent

Hutchinson-Gilford progeria syndrome (HGPS; OMIM#176670) is an ultra-rare disease
that may recapitulate some features of biological aging [20–24]. It has been reported
that the heterozygous, de novo point mutation c.1824C>T (p.G608G) (NM_170707.3) in
exon 11 of the human LMNA gene—which encodes Lamin A and C—mediates abnormal
alternative splicing [25–30] and generates an abnormal variant protein, Progerin (50-amino-
acid-deleted Lamin A), which is responsible for the nucleus deformation (Figure 1). The
variant (Progerin) was also reported to be present in non-HGPS aged cells by sporadic
mutation [31,32], which may be related to some aging diseases. It has been reported that
Progerin accumulates in diverse human cancer cells [33,34].
Lamin A is a nuclear structural protein associated with type-V intermediate filaments;
it is synthesized as a precursor named prelamin A and completed with a four-step modi-
fication. A 15-carbon farnesyl moiety is attached to the cysteine of the carboxyl-terminal
(CaaX motif) by farnesyltransferase (First). Zmpste24 metallopeptidase cleaves the last
three amino acids in CaaX motif (Second). A prenylprotein-specific methyltransferase
carboxyl-methylates the newly exposed farnesyl cysteine (Third). Finally, the metallopepti-
dase gets rid of the carboxyl 15 amino acids from the farnesylated and methylated prelamin
A, leading to the release of mature Lamin A without farnesyl and methyl group [35–37].
However, mutation-driven aberrant splicing makes Progerin keep the farnesylation at
its C-terminus because of the target site deletion of the metallopeptidase. Expression of
Progerin makes morphology changes in the cells, such as nucleus membrane blister, and
it also induces a decrease of nucleoplasmic Lamin A [27,38]. DNA damage from intrinsic
and extrinsic origin induces progressively cellular malfunction and creates vulnerabilities
Genes 2022, 13, 165 4 of 11

to developing chronic diseases related to aging. It has already been proven that reduction
of extrinsic DNA damaging, such as UV protection and to stop smoking, decreased the
development of age-related disease [39]. Alterations in Lamin A including HGPS have an
impact both on DNA transactions and epigenetic modifications. Therefore, it is supported
that Progerin-induced DNA damage or genomic instability contributes to the pathologies
of aging or aging-related diseases [40]. Reduction of Progerin expression induces nuclear
reformation [38,41], indicating that new or enhanced activity from Progerin is a causative
factor of HGPS. Particularly, the protein levels of Progerin and Lamin A/C are remark-
ably decreased in induced pluripotent stem cells derived from HGPS patients [42,43]. In
addition, cellular senescence markers such as nuclear deformation, tri-Methyl-Histone
H3 (Lys9), and senescence-associated β galactosidase (SA–β-gal) activity, are reduced in
the cells. On the other hand, differentiated HGPS cells express new senescence markers
and then express Progerin [42]. Despite several papers reporting the role of this protein
in cell-cycle regulation [27,44,45], premature aging [39,46,47], and senescence [41,48], how
precisely Progerin causes several cellular defects and aging remains to be elucidated. How-
ever, a farnesyltransferase (FT) has been suggested as a putative therapeutic target for
HGPS, and several groups showed that farnesyltransferase inhibitors (FTIs) blocked the
accumulation of Progerin and reduced its amount. They potentially ameliorated the disease
progression of HGPS and the processing-deficient progeroid laminopathies [49–51].
Lonafarnib (Zokinvy™) is an orally administrable biologically active FTI developed
from Eiger BioPharmaceuticals (Palo Alto, CA, USA) with permission from Merck & Co.
(Kenilworth, NJ, USA). It is produced for the medication of hepatitis D viral infections and
disorders caused by mutations in genes encoding proteins of the nuclear lamina (progeroid
laminopathies) [52]. Originally, Merck & Co. discovered the drug as an investigational drug
for the study of cancer, but the development of lonafarnib for cancer has been canceled
because of low efficacy [52]. More usefully, it was defined that it suppresses FT and prevents
farnesylation. Subsequently, it reduces the aggregation of Progerin-like proteins including
Progerin in the cells [51]. Two years ago, lonafarnib achieved a clinical approval in the US
for the sake of reduction the risk of mortality in HGPS and for the medication of progeroid
laminopathies, which are with the heterozygous Lamin A gene mutants or homozygous
or compound heterozygous mutations of ZMPSTE24 [53,54]. Indeed, a clinical trial of
lonafarnib verified that it is able to increase the lifespan of HGPS patients by around two
years [52], but the trial was carried out without a single-blind study. As a downside,
in vitro experiments in cells showed that its treatment has cytotoxic effects, resulting in
the deformation of the nuclei [55] and apoptotic cell death [56,57], which undermine its
favorable effect. Currently, more effective treatments with less side effects are required for
HGPS patients.

3. Future Therapeutic Agent for HGPS and Aging Cells

Park and his colleagues have studied age-related cancer progression and
Progerin [18,34,58]. They got the idea for a possible aberrant protein complex between
Lamin and Progerin that might cause the progeria disease. In proteomic studies, the Lamin
A/C was identified as an interacting protein with Progerin [59,60], which made them more
convinced of the possibility. Then, they speculated that the interaction between Progerin
and Lamin A/C might contribute to the senescence phenotype development of HGPS
and aged cells. In their report, they showed that the most important target of Progerin is
Lamin A/C, not Lamin B [19]. On this basis, using the chemical library, they screened new
allosteric three-chemical candidates that block the binding of Progerin and Lamin A/C
through direct interaction between the chemicals and Progerin (Figure 1). The chemicals
efficiently alleviated senescence properties including growth arrest, accumulation of SA–β-
gal, and nucleus deformation in HGPS cells. They did not have a therapeutic effect on the
Profigin-independent progeria model mice (Zmpste24–/–) but expanded the lifespan of the
HGPS model mice (Lmna+/G609G), representing the in vivo relevance of blocking Progerin–
Lamin A/C interaction as a new therapeutic strategy for HGPS. This study suggested that
Genes 2022, 13, 165 5 of 11

an optimization of chemicals that target the interface of Progerin-Lamin binding might

help to develop a promising medication for HGPS [19]. Thereafter, Park and his colleagues
tried medical chemistry using the candidate chemical and secured an advanced drug can-
didate, Progerinin (SLC-D011), in which the in vivo pharmacokinetics were improved. The
chemical could extend the lifespan of homozygous Lmna G609G mice by about 10 weeks.
Furthermore, heterozygous Lmna+/G609G mice treated by oral administration lived 14
weeks longer than the mice treated with lonafarnib (farnesyl-transferase inhibitor), which
could live for only around 2 weeks longer than the control [61]. Additional comparative
toxicological studies in mice, rats, and dogs demonstrated that SLC-D011 is safe to test in a
human clinical trial (NCT04512963).
Recently, several articles showed that the antisense oligonucleotide or base editing that
targets the point mutation c.1824C>T could rescue the aberrant splicing [62,63]. Diverse
engineered Cas9 variants recognizing the sequences of modified PAM and an enhanced
cleaving specificity have been evolved, and they may make it possible for us to expand
the selective scope of CRISPR/Base-editors [64–67], allowing single vector delivery by an
adeno-associated vector and demonstrating to be notably practical for medicinal appli-
cations. These give us an idea about the possibility of in vivo base-editing as potential
therapeutics for many genetic diseases including HGPS by directly fixing their main reason.
However, for human in vivo treatment, how much off-target effects on chromosomal level
can be reduced in base editing steps and how efficiently viral delivery system is able to
reduce side effects as like gene integration, immune activation, etc., remains to be properly
addressed.
Furthermore, they extended the effect of Progerinin to Werner syndrome, a rare
progressive genetic disorder that results from a functional defect of the human WRN
protein, a member of the RecQ DNA helicase family [68]. The Progerin-inhibitor (SLC-
D011) could ameliorate senescence in the fibroblasts and cardiomyocytes derived from
Werner syndrome-iPSCs, suggesting that Progerin is able to accumulate and cause aging
phenotype under WRN-deficient conditions and the phenomenon may be prevented by
SLC-D011 [69]. Interestingly, under the natural aging process, Progerin can be produced and
increased with age [47,70]. Natural aging and HGPS share common characteristics, such
as alopecia, osteolysis, atherosclerosis, and cardiovascular complications. Cardiovascular
problems are one of the most common causes of death in the elderly [71]. Progerinin
(SLC-D011) could reduce fibrosis in the hearts of Lmna G609G progeroid mice and also
improve their heart-beat rate [61]. These results suggest that SLC-D011 may reduce the
burden of cardiovascular disease in normal aging.

4. SCLC, Splicing Variant DX2, and Target Molecules

Human lung cancers consist of two groups—small cell lung cancer (SCLC) and non-
small cell lung cancer (NSCLC). NSCLC has three subsets: large cell lung cancer, squamous
cell lung carcinoma, and adenocarcinoma. Among human lung cancers, SCLC is involved
in around 20% of the cancers and has very aggressive properties. Smoking tobacco is
the typical threat for SCLC, and more than 90% of patients suffering from SCLC have
smoking experience [72–74]. SCLC has diverse genetic alterations, meaning it is genetically
unstable [75,76]. Most SCLC cells have variations in chromosome 3p and frequently
express mutations in oncogenes such as RB1, TP53, etc. [77,78]. The tendency toward early
dissemination, rapid tumor cell growth, and neuroendocrine features are the characteristics
of SCLC disease. Most patients (around 70%) show an extensive stage of disease (ES-SCLC)
at the time of diagnosis, and the remaining show a limited stage of disease (LS-SCLC).
SCLC has a poor prognosis, with an average survival of 10 months for ES-SCLC patients
and survival of around 4 years for LS-SCLC patients [79].
Immunotherapy using checkpoint inhibitors such as Pembrolizumab, which is a hu-
manized monoclonal antibody that binds the PD-1 receptor, and Nivolumab, which is a
fully human PD-1 immune checkpoint inhibitor antibody, has shown promising medici-
nal effects by modulating the immune microenvironment in SCLC [80,81]. Furthermore,
Genes 2022, 13, 165 6 of 11

combinations of chemotherapy and immunotherapy and other treatment, such as SRA737

plus low dose gemcitabine with anti-PD1 antibody, have currently been in clinical trials for
SCLC and other malignancies [82]. It has not been clearly understood whether the antigens
allowing the immune system can discriminate cancer cells from non-cancer cells. However,
recent studies have suggested that frameshifted peptides from RNA containing neo-open
reading frames can be an origin of neoantigens that give rise to a cancer-specific immune
response, expediting the development of novel therapeutics and selectively enhancing T
cell activation against neoantigens. [83–86]. However, there is no proper anticancer drug
with lower side effect against SCLC as of yet.
Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2), also
known as p38 and JTV-1, plays an important part in controlling cell fate and has an
anti-proliferative role through enhancing the TGF-β-driven growth-arrest signaling [87],
and it also elevates the cell death signaling via p53 or through TNF-α [88,89]. Because of
this, AIMP2-deficient mice experienced neonatal mortality by lung failure resulting from
the over-proliferation of pulmonary epithelial cells. Additionally, heterozygous mice, which
have a reduced expression of AIMP2, were highly susceptible to tumorigenesis [90]. These
results suggested that AIMP2 might be a haploinsufficient tumor suppressor with a unique
working mechanism. Different from the expected roles, housekeeping or a scaffolding on
the crucial multienzyme complex, it had diverse cellular functions such as acting as a p53
activator and substrate of Parkin [91,92]. The base substitution of A152 to G at its exon
2 region was found in cells transformed by carcinogens. The single mutation within splice
donor or the splice acceptor sites generated exon 2 skipping and led to the accumulation
of AIMP2-DX2 (also called DX2) in the cells (Figure 2). DX2, an aberrant splicing variant
of AIMP2, has been shown to be at higher abundance in human lung cancer [92,93] and
increased by benzopyrene [93], which exhibits genotoxic and carcinogenic effects associated
with smoking [94]. From this point, Park and his colleagues speculated that splicing variant
DX2 might be the critical factor of lung cancer initiation or progression, inspiring them
to study the DX2 function in human lung cancer, particularly, SCLC due to the strong
co-relation with smoking. They studied the expression patterns of DX2 in various human
lung cancer cell lines and reported that DX2 became stable by various oncogenic forms
of signaling including Her2/Neu-AKT or K-Ras activation. Then, they proved that DX2
could block the activation of oncogene-induced p14/ARF by direct binding, but not p53,
supporting the report about p14/ARF inactivation without genetic mutation in SCLC [95].
Thus, they speculated that one of the plausible target points at which to treat SCLC was to
prevent DX2 from binding to p14/ARF. Their next step was screening chemicals inhibiting
the interaction between DX2 and p14/ARF. Through ELISA-based chemical screening,
they found a small chemical inhibitor (SLCB050) blocking the interaction and additionally
increasing p14/ARF and suppressing DX2 (Figure 2). It also suppressed the cell viabil-
ity of SCLC cell lines with the p14/ARF-dependent manner [18]. They further showed
its significantly enhanced anti-cancer effect in DX2/K-RasLA2 double-transgenic (DK)
mice when treated together with GN25, inhibiting the binding of p53-Snail [96] or with
Adriamycin, having antimitotic and cytotoxic activity in various cancer cells [18,97]. The
chemical SLCB050 is being developed by making derivatives to improve the drug potency,
efficacy, and bioavailability (BA). It is believed that the DX2 inhibitor is another example
reflecting how aberrant protein–protein interfaces formed by a splicing variant in disease
cells can make for an efficient drug targeting site.

5. Conclusions
The complex network of direct interactions between proteins, known as the inter-
actome, and the balanced homeostatic status in cellular protein systems, known as pro-
teostasis, have been widely recognized as important concepts for therapeutic targets for
various diseases. Alternative splicing is involved in gene regulation and diversification
by increasing its coding potential [12–15]. The disruption of the balance among splicing
variants or neomorphic protein complexes by unusual alternative splicing variants may
Genes 2022, 13, 165 7 of 11

lead to pathological disorders. However, it is not evident whether disease induction is

generated by a change in alternative splicing or whether the change just indicates a basic
defect. Therefore, further studies into PPI networks, and research that defines the global
proteostasis of cells, are necessary to provide a better interpretation of the fundamental
cellular biochemistry and physiology of diseases. In this regard, new findings of unusual
splicing variants linked to human diseases and of ways to address their pathogenic mecha-
nisms might give us better insights into the diagnosis and therapy of diseases. Therefore,
it is important to examine culprit genes where aberrant alternative splicing events are
induced when exposed to stresses such as aging, genetic changes, carcinogens, etc., to
support the development of pharmacological interventions against many diseases that do
not have treatments to date. In this review, using the examples of SCLC and HGPS, we
focused specifically on small molecules that inhibit protein–protein interactions (PPIs) by
interacting directly with one protein partner from a splicing variant, rather than binding
at functional sites of the other partners. We hope that this review may have meaningful
ramifications to biologists developing chemical PPI inhibitors.

Author Contributions: Conceptualization, B.-H.K., and B.-J.P.; investigation, B.-H.K., T.-G.W., S.-
M.K., S.P.; writing—original draft preparation, B.-H.K.; writing—review and editing, T.-G.W., S.-M.K.,
S.P.; visualizing, S.-M.K., S.P.; supervision, B.-J.P. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: This work was supported by a two year research grant from Pusan National
University (2021–2023).
Conflicts of Interest: The authors declare no conflict of interest.

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