Hui-Kuan eLin

Wenyi eWei

Wenyi Wei

Hui-Kuan Lin

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Frontiers in Oncology

The key role of ubiquitination and sumoylation in signaling and cancer: a research topic

Lin, Hui-Kuan

Wei, Wenyi

Harvard University - DASH 

 The Key Role of Ubiquitination and Sumoylation in Signaling andCancer: A Research Topic  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Wei, Wenyi, and Hui-Kuan Lin. 2012. The key role ofubiquitination and sumoylation in signaling and cancer: aresearch topic. Frontiers in Oncology 2:187.Published Version doi:10.3389/fonc.2012.00187Accessed February 19, 2015 11:55:31 AM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10579228Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAEDITORIALpublished: 05 December 2012doi: 10.3389/fonc.2012.00187The key role of ubiquitination and sumoylation in signalingand cancer: a research topicWenyi Wei1*a n dHui-Kuan Lin2,3*1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA2 Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA3 Graduate School of Biomedical Sciences, The University of Texas, Houston, TX, USA*Correspondence: wwei2@bidmc.harvard.edu; hklin@mdanderson.orgEdited by:Lorenzo Galluzzi, Institut National de la Santé et de la Recherche Medicale, FranceINTRODUCTIONUbiquitination and sumoylation are two important post-translationalmodiﬁcationsthatplaypivotal rolesinsignalingreg-ulation, protein trafﬁcking, protein stability, and transcriptionalregulation, ultimately regulating a plethora of biological pro-cesses such as cell survival, cell migration, DNA damage response(DDR), neurodegeneration, and cancer. Although ubiquitinationis traditionally viewed as a critical mark targeting proteins forproteasome-dependent degradation, recent studies have revealedthat it also has non-proteolytic functions. In contrast, sumoyla-tion is long thought not to target proteins for degradation, butaccumulating evidence suggestst h a ti tc a ns e r v ea sap r i m i n gpre-requisite forubiquitination,therebyinducingproteinubiqui-tination and degradation. Thus, there is an important cross-talkbetween sumoylation and ubiquitination in determining proteinfate. Deregulation in these two processes may cause aberrantactivity of proteins and in turn contributes to cancer develop-ment. In this Research Topic, we assembled 10 review articles todiscuss the role of these two post-translational modiﬁcations inregulating diverse signal transduction pathways, thereby provid-ing novel insights in unraveling the puzzle as to how they mayregulate cancer progression.The ubiquitin-proteasome system has been recently charac-terized as a major regulatory mechanism for ensuring orderedand coordinated cell cycle progression by selective degradationof key cell cycle regulators. Two related, multi-subunit E3 ubiq-uitin ligase enzymes, the Anaphase Promoting Complex (APC)and the Skp1-Cullin1-F-box complex (SCF) are thought to be themajordriving forces governingcell cycleprogression. Nagi Ayad’sgroup discussed the important physiological functions of APC/Cas well as the upstream signaling pathway that governs the timelyregulation of APC/C. Given the critical role of APC/C in cell pro-liferation and development, they also illustrated the emergingcontribution of APC/C in tumorigenesis and proposed APC/Cintervention as a potential anti-cancer therapeutic approach.Among the SCF-type of E3 ubiquitin ligases, SCFSkp2 is oneof the most well-studied E3 ligases and Skp2 overexpression isfrequently observed in various types of human cancers includingbreast cancer. The Wei group recently summarized the oncogenicrole of Skp2 in breast cancer development. The interplay betweenSkp2 and other major signaling pathways as well as the recentadvances in identifying Skp2 downstream substrates were alsodiscussed. Lastly, they proposed speciﬁc Skp2 inhibitors as novelanti-breast cancer agents.Unlike Skp2, VHL forms a distinct type of E3 ligase by asso-ciating with Elongin B, Elongin C, and Cullin 2. The Yanggroup discussed the important role of VHL in hypoxia sensingand kidney disease development by targeting HIF for ubiquiti-nation and destruction in a hydroxylation-dependent manner.They also summarized the recent advances in understanding thetumor suppressor role of VHL independent of HIF. The identi-ﬁcation of novel VHL substrates including PKC and EGFR andtheir relevance to signaling and cancer development were alsodiscussed.In addition to associating with VHL, the Elongin B/C com-plex can also interact with the SOCS box-containing proteinsand Cullin 2 or Cullin 5 to form distinct functional E3 ubiq-uitin ligases. The Takumi Kamura group contributed a com-prehensive review that described the recent advances in furthercharacterizing the assembly as well as the physiological func-tions of the Elongin B/C-containing E3 ligases, which are furtherdivided into the Cullin 2-type and the Cullin 5-type. They alsosummarized the newly identiﬁed downstream substrates, whichprovided an important insight into the critical roles of ElonginB/C-containing E3 ligases in regulating a variety of cellularfunctions.The Pengbo Zhou group summarized the recent progressin functional analysis of another major class of E3 ubiqutinligases, the Cullin 4-containing (CRL4) family of ligases. Inthis review, the authors updated the recent understanding ofthe two Cullin 4 family members, Cullin 4A and Cullin 4Bin human cancer and neuronal disease development. In addi-tion, the recent advances in identifying novel substrates forvarious Cullin 4-containing E3 ligases that typically associatewith a speciﬁc DDB1-Cullin 4 associated factor (DCAF) werefurther discussed. More importantly, given their critical rolesin tumorigenesis, the authors speculated that Cullin 4A andCullin 4B could be potentially pursued as new targets for cancerprevention.Protein kinases such as Akt, MAPK, and IKK are commonlyupregulated and/or activated in a variety of human cancers. TheHung group summarized recent advances of howthese oncogenickinases regulate protein ubiquitination and degradation. Theyproposed that protein phosphorylation induced by these kinasesprovides a scaffold for the recognition of ubiquitin ligases (E3s),thereby eliciting protein ubiquitination and degradation. Severaloncogenic proteins, such as β-catenin, MCL-1, and Snail, knownto be regulated by these oncogenic kinases, were also discussed.www.frontiersin.org December 2012 | Volume 2 | Article 187 | 1Wei and Lin Ubiquitination and sumoylation in cancerIn addition to kinase regulation, ubiquitination can alsoorchestrate DDR by controlling protein degradation and non-proteolytic pathways. DDR triggers serial signaling events thatare involved in DNA damage repair, transcription regulation,growth arrest, and apoptosis. The Jin group discussed the roleof Cullin/RING ubiquitination ligase 1 (CRL1) and CRL4 inmultiple steps of the DDR by regulating protein stability. TheYan group further illustrated the role of histone ubiquitina-tion and deubiquitination in regulating transcription and DDR.The E3 ligases and deubiquitinating enzymes regulating the his-tone ubiquitination and deubiquitination processes and DDR arediscussed.Like protein ubiquitination and phosphorylation, sumoy-lation is another important post-translational modiﬁcationthat is also critically involved in DDR. Upon DNA damage,sumoylation of proteins like 53BP1 and BRCA-1 involved inDDR and DNA repair is induced and may play a role inDDR by inducing its E3 ligase activity. David Ann and col-leagues discussed the potential crosstalk between sumoylationand ubiquitination and speculated that RNF4 may be a crit-ical E3 ligase that connects the sumoylation and ubiquitina-tion crosstalk to participate in ATM-mediated signaling andDDR.Although ubiquitination is traditionally viewed as a criti-cal marker targeting proteins for proteasome-dependent degra-dation, recent studies reveal that it also plays non-proteolyticfunctions. K48-linked ubiquitination in general leads to proteindegradation, while K63-linked ubiquitination fails to do so. TheLin group and colleagues focused on a new type of ubiquitina-tion called K63-linked ubiquitination and proposed that K63-linked ubiquitination serves as an important activation markfor oncogenic kinase activation, thereby contributing to cancerdevelopment. Thus, targeting K63-linked ubiquitination may beemployed for cancer therapy.ACKNOWLEDGMENTSThis work is supported by Department of Defense ProstateCancer Research Program grant and National Institutes ofHealth (NIH) RO1 grants to Wenyi Wei, MD Anderson ResearchTrust Scholar Fund, NIH RO1 grants and CPRIT grant toHui-Kuan Lin.Received: 02 October 2012; accepted: 19 November 2012; published online: 05December 2012.Citation: Wei W and Lin H-K (2012) The key role of ubiquitination andsumoylation in signaling and cancer: a research topic. Front. Oncol. 2:187. doi:10.3389/fonc.2012.00187Thisarticle wassubmitted toFrontiers in MolecularandCellularOncology,a specialtyof Frontiers in Oncology.Copyright © 2012 Wei and Lin. This is an open-access article distributed under theterms of the Creative Commons Attribution License, which permits use, distribu-tion and reproduction in other forums, provided the original authors and source arecredited and subject to any copyright notices concerning any third-party graphics etc.Frontiers in Oncology | Molecular and Cellular Oncology December 2012 | Volume 2 | Article 187 | 2

The Key Role of Ubiquitination and Sumoylation in Signaling and Cancer: A Research Topic

Frontiers - Publisher Connector

EDITORIAL
published: 05 December 2012
doi: 10.3389/fonc.2012.00187
The key role of ubiquitination and sumoylation in signaling
and cancer: a research topic
Wenyi Wei1* and Hui-Kuan Lin2,3*
1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2 Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA
3 Graduate School of Biomedical Sciences, The University of Texas, Houston, TX, USA
*Correspondence: wwei2@bidmc.harvard.edu; hklin@mdanderson.org
Edited by:
Lorenzo Galluzzi, Institut National de la Santé et de la Recherche Medicale, France
INTRODUCTION
Ubiquitination and sumoylation are two important post-
translationalmodifications that play pivotal roles in signaling reg-
ulation, protein trafficking, protein stability, and transcriptional
regulation, ultimately regulating a plethora of biological pro-
cesses such as cell survival, cell migration, DNA damage response
(DDR), neurodegeneration, and cancer. Although ubiquitination
is traditionally viewed as a critical mark targeting proteins for
proteasome-dependent degradation, recent studies have revealed
that it also has non-proteolytic functions. In contrast, sumoyla-
tion is long thought not to target proteins for degradation, but
accumulating evidence suggests that it can serve as a priming
pre-requisite for ubiquitination, thereby inducing protein ubiqui-
tination and degradation. Thus, there is an important cross-talk
between sumoylation and ubiquitination in determining protein
fate. Deregulation in these two processes may cause aberrant
activity of proteins and in turn contributes to cancer develop-
ment. In this Research Topic, we assembled 10 review articles to
discuss the role of these two post-translational modifications in
regulating diverse signal transduction pathways, thereby provid-
ing novel insights in unraveling the puzzle as to how they may
regulate cancer progression.
The ubiquitin-proteasome system has been recently charac-
terized as a major regulatory mechanism for ensuring ordered
and coordinated cell cycle progression by selective degradation
of key cell cycle regulators. Two related, multi-subunit E3 ubiq-
uitin ligase enzymes, the Anaphase Promoting Complex (APC)
and the Skp1-Cullin1-F-box complex (SCF) are thought to be the
major driving forces governing cell cycle progression. Nagi Ayad’s
group discussed the important physiological functions of APC/C
as well as the upstream signaling pathway that governs the timely
regulation of APC/C. Given the critical role of APC/C in cell pro-
liferation and development, they also illustrated the emerging
contribution of APC/C in tumorigenesis and proposed APC/C
intervention as a potential anti-cancer therapeutic approach.
Among the SCF-type of E3 ubiquitin ligases, SCFSkp2 is one
of the most well-studied E3 ligases and Skp2 overexpression is
frequently observed in various types of human cancers including
breast cancer. The Wei group recently summarized the oncogenic
role of Skp2 in breast cancer development. The interplay between
Skp2 and other major signaling pathways as well as the recent
advances in identifying Skp2 downstream substrates were also
discussed. Lastly, they proposed specific Skp2 inhibitors as novel
anti-breast cancer agents.
Unlike Skp2, VHL forms a distinct type of E3 ligase by asso-
ciating with Elongin B, Elongin C, and Cullin 2. The Yang
group discussed the important role of VHL in hypoxia sensing
and kidney disease development by targeting HIF for ubiquiti-
nation and destruction in a hydroxylation-dependent manner.
They also summarized the recent advances in understanding the
tumor suppressor role of VHL independent of HIF. The identi-
fication of novel VHL substrates including PKC and EGFR and
their relevance to signaling and cancer development were also
discussed.
In addition to associating with VHL, the Elongin B/C com-
plex can also interact with the SOCS box-containing proteins
and Cullin 2 or Cullin 5 to form distinct functional E3 ubiq-
uitin ligases. The Takumi Kamura group contributed a com-
prehensive review that described the recent advances in further
characterizing the assembly as well as the physiological func-
tions of the Elongin B/C-containing E3 ligases, which are further
divided into the Cullin 2-type and the Cullin 5-type. They also
summarized the newly identified downstream substrates, which
provided an important insight into the critical roles of Elongin
B/C-containing E3 ligases in regulating a variety of cellular
functions.
The Pengbo Zhou group summarized the recent progress
in functional analysis of another major class of E3 ubiqutin
ligases, the Cullin 4-containing (CRL4) family of ligases. In
this review, the authors updated the recent understanding of
the two Cullin 4 family members, Cullin 4A and Cullin 4B
in human cancer and neuronal disease development. In addi-
tion, the recent advances in identifying novel substrates for
various Cullin 4-containing E3 ligases that typically associate
with a specific DDB1-Cullin 4 associated factor (DCAF) were
further discussed. More importantly, given their critical roles
in tumorigenesis, the authors speculated that Cullin 4A and
Cullin 4B could be potentially pursued as new targets for cancer
prevention.
Protein kinases such as Akt, MAPK, and IKK are commonly
upregulated and/or activated in a variety of human cancers. The
Hung group summarized recent advances of how these oncogenic
kinases regulate protein ubiquitination and degradation. They
proposed that protein phosphorylation induced by these kinases
provides a scaffold for the recognition of ubiquitin ligases (E3s),
thereby eliciting protein ubiquitination and degradation. Several
oncogenic proteins, such as β-catenin, MCL-1, and Snail, known
to be regulated by these oncogenic kinases, were also discussed.
www.frontiersin.org December 2012 | Volume 2 | Article 187 | 1
Wei and Lin Ubiquitination and sumoylation in cancer
In addition to kinase regulation, ubiquitination can also
orchestrate DDR by controlling protein degradation and non-
proteolytic pathways. DDR triggers serial signaling events that
are involved in DNA damage repair, transcription regulation,
growth arrest, and apoptosis. The Jin group discussed the role
of Cullin/RING ubiquitination ligase 1 (CRL1) and CRL4 in
multiple steps of the DDR by regulating protein stability. The
Yan group further illustrated the role of histone ubiquitina-
tion and deubiquitination in regulating transcription and DDR.
The E3 ligases and deubiquitinating enzymes regulating the his-
tone ubiquitination and deubiquitination processes and DDR are
discussed.
Like protein ubiquitination and phosphorylation, sumoy-
lation is another important post-translational modification
that is also critically involved in DDR. Upon DNA damage,
sumoylation of proteins like 53BP1 and BRCA-1 involved in
DDR and DNA repair is induced and may play a role in
DDR by inducing its E3 ligase activity. David Ann and col-
leagues discussed the potential crosstalk between sumoylation
and ubiquitination and speculated that RNF4 may be a crit-
ical E3 ligase that connects the sumoylation and ubiquitina-
tion crosstalk to participate in ATM-mediated signaling and
DDR.
Although ubiquitination is traditionally viewed as a criti-
cal marker targeting proteins for proteasome-dependent degra-
dation, recent studies reveal that it also plays non-proteolytic
functions. K48-linked ubiquitination in general leads to protein
degradation, while K63-linked ubiquitination fails to do so. The
Lin group and colleagues focused on a new type of ubiquitina-
tion called K63-linked ubiquitination and proposed that K63-
linked ubiquitination serves as an important activation mark
for oncogenic kinase activation, thereby contributing to cancer
development. Thus, targeting K63-linked ubiquitination may be
employed for cancer therapy.
ACKNOWLEDGMENTS
This work is supported by Department of Defense Prostate
Cancer Research Program grant and National Institutes of
Health (NIH) RO1 grants to Wenyi Wei, MD Anderson Research
Trust Scholar Fund, NIH RO1 grants and CPRIT grant to
Hui-Kuan Lin.
Received: 02 October 2012; accepted: 19 November 2012; published online: 05
December 2012.
Citation: Wei W and Lin H-K (2012) The key role of ubiquitination and
sumoylation in signaling and cancer: a research topic. Front. Oncol. 2:187. doi:
10.3389/fonc.2012.00187
This article was submitted to Frontiers in Molecular and Cellular Oncology, a specialty
of Frontiers in Oncology.
Copyright © 2012 Wei and Lin. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits use, distribu-
tion and reproduction in other forums, provided the original authors and source are
credited and subject to any copyright notices concerning any third-party graphics etc.
Frontiers in Oncology | Molecular and Cellular Oncology December 2012 | Volume 2 | Article 187 | 2


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