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Epigenetic regulation of p62/SQSTM1 overcomes the radioresistance of head and neck cancer cells via autophagy-dependent senescence induction

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Abstract
Tumors are composed of subpopulations of cancer cells with functionally distinct features. Intratumoral heterogeneity limits the therapeutic effectiveness of cancer drugs. To address this issue, it is important to understand the regulatory mechanisms driving a subclonal variety within a therapy-resistant tumor. We identified tumor subclones of HN9 head and neck cancer cells showing distinct responses to radiation with different levels of p62 expression. Genetically identical grounds but epigenetic heterogeneity of the p62 promoter regions revealed that radioresistant HN9-R clones displayed low p62 expression via the creation of repressive chromatin architecture, in which cooperation between DNMT1 (DNA methyltransferases 1) and HDAC1 (histone deacetylases 1) resulted in DNA methylation and repressive H3K9me3 and H3K27me3 marks in the p62 promoter. Combined inhibition of DNMT1 and HDAC1 by genetic depletion or inhibitors enhanced the suppressive effects on proliferative capacity and in vivo tumorigenesis following irradiation. Importantly, ectopically p62-overexpressed HN9-R clones increased the induction of senescence along with p62-dependent autophagy activation. These results demonstrate the heterogeneous expression of p62 as the key component of clonal variation within a tumor against irradiation. Understanding the epigenetic diversity of p62 heterogeneity among subclones allows for improved identification of the functional state of subclones and provides a novel treatment option to resolve resistance to current therapies.
Author(s)
김상윤김승후남혜윤이명진이원혁장은주조경자최경철한명월Geun-Hee LeeGi-Jun SungHee-Bum Kang
Issued Date
2021
Type
Article
Keyword
AutophagyCancer therapiesChromatinCloningDeoxyribonucleic acid--DNADNA methylationDNMT1 proteinEpigeneticsHead & neck cancerHead and neck cancerHistonesPhagocytosisRadioresistanceSenescenceSubpopulationsTumorigenesis
DOI
10.1038/s41419-021-03539-5
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7798
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_461281e556144b34b404b42b1c0e8861&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Epigenetic%20regulation%20of%20p62%2FSQSTM1%20overcomes%20the%20radioresistance%20of%20head%20and%20neck%20cancer%20cells%20via%20autophagy-dependent%20senescence%20induction&offset=0&pcAvailability=true
Publisher
CELL DEATH DISEASE
Location
영국
Language
영어
ISSN
2041-4889
Citation Volume
12
Citation Number
3
Citation Start Page
0
Citation End Page
0
Appears in Collections:
Medicine > Medicine
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