Abstract

Cellularsenescenceisatumorsuppressivecellgrowtharresttriggeredbyinducerssuchas activationofoncogenesandchemotherapeutics.However,senescentcellsareviableandmaypromote tumorprogressionandtherapyrelapsethroughsecretionoffactorssuchascytokines,chemokinesand growthfactors,termedthesenescence-associatedsecretoryphenotype(SASP).Thus,itwouldbeideal toenhancesenescence-associatedgrowtharrestwhilelimitingSASPbecausethismayleadtoadurable therapeuticoutcome.Notably,itremainstobedeterminedwhethersilencingofproliferationgenesand upregulationofSASPgenesarecoupledatthemolecularlevel.Thus,theoverallgoalofthisproposalis toinvestigatethemechanismthatcoordinatesthesilencingofproliferationgenesandtheupregulationof SASPgenesduringsenescenceanditsimplicationsincancerandresponsetotherapy.HMGB2isa chromatinarchitectureproteinthatbindstoDNAwithoutsequencespecificity.Ourpreliminarydata suggestthatHMGB2orchestratesgeneexpressionreprogrammingduringsenescencebyactingasa molecularswitch.Specifically,lossofHMGB2fromgenomiclociofproliferationgenescontributestotheir silencing.Incontrast,HMGB2?sredistributiontoSASPgeneslocipromotestheirexpression.Consistent withitsroleinsenescence,HMGB2isoftenupregulatedinepithelialovariancancer(EOC)andits expressioncorrelateswithEOCprogression.Further,expressionofHMGB2positivelycorrelateswithits targetproliferationgenesinEOCs.Basedonthesefindings,ourcentralhypothesisisthatHMGB2 orchestratesgeneexpressionreprogrammingtoregulatetheswitchfromproliferationtosenescence. WealsohypothesizethatHMGB2contributestoEOCbysuppressingsenescenceandpromotes platinum-basedtherapyrelapsebydrivingSASP.Accordingly,twospecificaimsareproposed:
Aim1 : ToelucidatethemolecularmechanismbywhichHMGB2regulatessenescence;?andAim2:To determinetheroleofHMGB2inEOCandtherapyrelapse.Theproposedstudiesarehighlynovel becausethisisthefirststudytoexploreanovelmolecularmechanismthatorchestratesthesilencingof proliferation-promotinggenesandtheupregulationofSASPgenesduringsenescence.Thus,ourstudies areparadigmshiftingintheirpotentialtoelucidatethemolecularbasisofgeneexpression reprogrammingduringsenescence.Theresearchproposedisofhighimpactbecausetheywilllaythe criticalfoundationforultimatelydevelopingnovelstrategiesthatharnessthetumor-suppressivebenefitof senescence,whilelimitingthedetrimentalaspectsofSASPtoultimatelyachievedurabletherapy outcome.Therefore,thecurrentstudywillnotonlyprovidecriticalmechanisticinsightsintogene expressionreprogrammingduringsenescence,butwillalsohavefar-reachingimplicationsforthe developmentofsenescence-basedtherapeuticstrategies.

Public Health Relevance

Theproposedresearchisrelevanttopublichealthbecauseitwillrevealacriticalmolecular switchthatcontrolscellularsenescence,animportanttumorsuppressionmechanism.Thesemolecular insightsmayprovidescientificrationaletoultimatelydevelopnovelstrategieswithadurabletherapeutic outcomeforcancersincludingovariancancer,themostlethalgynecologicalmalignancyintheUnited States.Therefore,theproposedresearchisrelevanttothepartoftheNIH?smissionthatpertainsto developingfundamentalknowledgethatwillreducetheburdenofhumanillness.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160331-07
Application #
9527749
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
2012-06-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Wu, Shuai; Fatkhutdinov, Nail; Fukumoto, Takeshi et al. (2018) SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells. Nat Commun 9:4116
Fukumoto, Takeshi; Magno, Elizabeth; Zhang, Rugang (2018) SWI/SNF Complexes in Ovarian Cancer: Mechanistic Insights and Therapeutic Implications. Mol Cancer Res 16:1819-1825
Karakashev, Sergey; Zhu, Hengrui; Wu, Shuai et al. (2018) CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun 9:631
Fukumoto, Takeshi; Park, Pyoung Hwa; Wu, Shuai et al. (2018) Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer. Cell Rep 22:3393-3400
Karakashev, Sergey; Zhu, Hengrui; Yokoyama, Yuhki et al. (2017) BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer. Cell Rep 21:3398-3405
Bitler, Benjamin G; Wu, Shuai; Park, Pyoung Hwa et al. (2017) ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19:962-973
Nacarelli, Timothy; Liu, Pingyu; Zhang, Rugang (2017) Epigenetic Basis of Cellular Senescence and Its Implications in Aging. Genes (Basel) 8:
Kim, Hyoung; George, Erin; Ragland, Ryan et al. (2017) Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models. Clin Cancer Res 23:3097-3108
Zhu, Hengrui; Le, Linh; Tang, Hsin-Yao et al. (2017) Detection of the Ubiquitinome in Cells Undergoing Oncogene-Induced Senescence. Methods Mol Biol 1534:127-137
Svoronos, Nikolaos; Perales-Puchalt, Alfredo; Allegrezza, Michael J et al. (2017) Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells. Cancer Discov 7:72-85

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