Targeting oral cancer epigenome via LSD1

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Oral squamous cell carcinoma (OSCC) accounts for the
majority of head and neck cancers. Treatment for OSCC
frequently comprises a combination of surgery, radio-
therapy, and chemotherapy. However, resistance to
therapy complicates treatment, and the 5-year survival
rate remains at ~65 percent. Understanding contributors
to disease progression and treatment resistance is
needed to promote patient outcomes. Lysine-specific
demethylase 1 (LSD1) is an amine oxidase with de-
methylase activity and has been implicated in maintain-
ing the undifferentiated state of cancer-initiating cells.
We have determined that lysine-specific demethylase 1
(LSD1) promote growth and metastasis of human and
mouse OSCC [1, 2].
LSD1 expression is elevated in clinical OSCC
compared to dysplastic and hyperplastic tissue speci-
mens, and is absent in adjacent normal tissues. In a
tissue microarray containing a diverse population of 80
OSCC (different grade/stage) of the larynx, tongue, and
submandibular gland, LSD1 staining positively
correlated with disease grade. Indeed, bioinformatics
analysis of mRNA expression data from The Cancer
Genome Atlas (TCGA) (from more than 300 OSCC)
confirmed that LSD1 expression increases with tumor
stage and grade.
We have established OSCC mouse models for
understanding the basic mechanism and therapeutic pre-
clinical applications [1-5]. We found that LSD1
knockdown in implanted HSC-3 orthotopic tumors
attenuates tumor growth and metastasis, whereas over-
expression of LSD1 promotes disease progression.
Further, small molecule inhibitors (e.g., GSK-LSD1) of
LSD1 attenuate disease progression, EGFR-induced
signaling, and tumor-promoting gene expression
(MMP13, LOXL4, and CTGF) in patient-derived
xenografts. Microarrays followed by gene set enrich-
ment analysis also showed that GSK-LSD1 inhibits key
mediators of OSCC [1].
LSD1 has a dual and context-dependent role in
transcriptional regulation Notch signaling [6] and
regulation of androgen receptor in prostate cancer [7].
LSD1 can demethylate H3K4 during gene repression and
H3K9 during gene activation. LSD1 demethylates his-
tone and non-histone genes by removing mono- and di-
methyl groups from histone H3 at lysine 4 (H3K4me1/2)
without affecting trimethylation. Inactivation of LSD1
promotes G1 arrest and induces differentiation-specific
Editorial
genes by selectively modulating the methylation states
of H3K4 and H3K9. Thus, expression of LSD1 may
enable epigenetic regulation of its targets, and
identifying LSD1-regulated molecular signaling
mechanisms could reveal new targets for OSCC
therapy. We recently implicated LSD1 in a novel action
with the Hippo signaling effector Yes-Associated
Protein (YAP), EGFR, NF-kB, and epithelial-mesen-
chymal transition in OSCC. GSK-LSD1 blocks YAP-
induced oncogenic signaling pathways in patient-
derived tonsillar epithelial, myoepithelial, and osteo-
sarcoma tumor cells. YAP and TAZ, key effectors of
the Hippo pathway, drive pro-tumorigenic signals in
OSCC [5]. GSK-LSD1 inhibits YAP-activated down-
stream targets such as SERPINE1 and CTGF in micro-
array analysis. However, which genes are functional
targets of LSD1 and exert the effects on these signaling
pathways—ultimately promoting OSCC progression
and metastasis—is not known.
EGFR signaling is implicated in OSCC progression
metastasis and therapeutic resistance. Inhibition of
LSD1 attenuates proliferation and EGF-induced signal-
ing, phospho-AKT, and ERK1/2 as well as NF-kB and
its associated transcriptional networks. Further, GSK-
LSD1 attenuates NF-kB signaling, which is implicated
in inflammatory signaling pathways and checkpoint
regulation. Although GSK-LSD1 attenuates NF-KB
signaling, whether it attenuates downstream inflamma-
tory effectors is not known.
Taken together, these results led us to ask the following
questions (Figure 1): Is LSD1 a key mediator of the pro-
inflammatory response in OSCC? Does LSD1 regulate
OSCC-specific mechanisms, and if so, can it be
exploited for monotherapy or combination therapies?
Our long-term objectives are to understand the LSD1-
induced molecular mechanism(s) underlying OSCC
growth and metastasis and to identify its therapeutic
potential for this disease. Epigenetic inhibitors that
could reset the OSCC epigenome may synergistically
correct deleterious effects induced by somatic mutations
or oncogenic pathways. Currently, various LSD1
inhibitors, including GSK-LSD1 (GlaxoSmithKline)
[8], are in phase 1 clinical trials for other cancer. LSD1
induced novel OSCC specific mechanisms, chemical
and biologic inhibitors under development to interfere
aberrant biological function of LSD1 could be applied
to OSCC therapy. Epigenetic targetting of OSCC via
TargetingoralcancerepigenomeviaLSD1
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ManishV.Bais
www.aging‐us.com  AGING2017,Vol.9,No. 12
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LSD1 may have broader implications for other tumor
types and translational studies.
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ManishV.Bais:DepartmentofMolecularandCellBiology,
BostonUniversityHenryM.GoldmanSchoolofDental
Medicine,Boston,MA02118,USA
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Correspondence:ManishV.Bais
Email:bmanish@bu.edu
Keywords:LSD1,epigenetics,oralcancer,OSCC
mechanism
Acknowledgements:TheauthoracknowledgesNIH/NIDCR
(R03DE025274),OralCancerAffinityResearchCollabora‐
tiveARC(EPOCARCaccount9950000118),CTSIpilotand
CenterofNanosciencefundingtoManishV.Bais
Copyright:Bais.Thisisanopen‐accessarticledistributed
underthetermsoftheCreativeCommonsAttribution
License(CCBY3.0),whichpermitsunrestricteduse,
distribution,andreproductioninanymedium,provided
theoriginalauthorandsourcearecredited

Received:December9,2017
Published:December11,2017
Figure1.ThepotentialroleofLSD1growth,metastasis,
andpro‐inflammatoryresponsetoOSCC.Ourstudies
showedthatLSD1expressionorrecruitmenttochromatinis
inducedbyEGFR‐ orYAP‐inducedsignalingpathways.LSD1
mayinducedemethylationofdimethylatedH3K4/H3K9or
alterNF‐kBsignaling,resultinginexpressionofMMP13,
LOXL4,andCTGF.Thecoordinationofdifferentsignaling
pathwaysregulatedbyLSD1couldleadtoOSCCgrowth,
metastasis,andapro‐inflammatoryresponse.AnLSD1
inhibitor(GSK‐LSD1)thatattenuatesLSD1functioncould
therebyinhibitOSCC.Unknownrolesareindicatedby(?).
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