HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway
The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However,...
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| Veröffentlicht in: | Cancer letters 2018-02, Vol.415, p.164-176 |
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| container_title | Cancer letters |
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| creator | Yang, Wei Liu, Yingying Gao, Ruoling Yu, Hongquan Sun, Ting |
| description | The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on stemness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSCs comparing to non-stem tumor cells. Inhibiting HDAC6 downregulated glioma-associated oncogene homolog 1 (Gli1), Patched (Ptch1 and Ptch2) receptors, components of SHH signal, expression and activity in GSCs. Restraining HDAC6 decreased cell proliferation, induces differentiation and increased apoptosis of GSCs via inactivation of SHH/Gli1 signaling pathway. Moreover, HDAC6 inhibition decreased DNA damage repair capacity of GSCs through degradation of checkpoint kinase (CHK) 1 caused by X-linked inhibitor of apoptosis (XIAP) downregulation, leading to elevated radiosensitivity. Taken together, these findings indicate that HDAC6 inhibition decreased stemness of GSCs and enhanced GSCs radiosensitivity through inactivating SHH/Gli1 pathway. This provides a promising novel drug target to overcome GSCs stemness and radioresistance.
•HDAC6i decreased stemness of GSCs.•HDAC6i enhanced GSCs radiosensitivity via inactivating SHH/Gli1 pathway.•HDAC6i decreased DDR of GSCs via CHK1/XIAP pathway. |
| doi_str_mv | 10.1016/j.canlet.2017.12.005 |
| format | Article |
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•HDAC6i decreased stemness of GSCs.•HDAC6i enhanced GSCs radiosensitivity via inactivating SHH/Gli1 pathway.•HDAC6i decreased DDR of GSCs via CHK1/XIAP pathway.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2017.12.005</identifier><identifier>PMID: 29222038</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Apoptosis ; Autophagy ; Brain cancer ; Brain tumors ; Cancer therapies ; Cell culture ; Cell proliferation ; Chemotherapy ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Epidermal growth factor ; Gli1 ; Glioblastoma ; Glioma ; Glioma cells ; Gloima stem cells ; HDAC6 ; Hedgehog pathway ; Histone deacetylase ; Homology ; Inactivation ; Inhibition ; Inhibitor drugs ; Kinases ; Laboratories ; Patients ; Protein expression ; Proteins ; Radiation ; Radiation therapy ; Radioresistance ; Radiosensitivity ; Signal transduction ; Stem cells ; Tumor cells ; Tumors ; XIAP protein</subject><ispartof>Cancer letters, 2018-02, Vol.415, p.164-176</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><rights>2017. Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-a86247fcc89597f0a9e1c98d904a3e70507727b5a92d200cfceb3a150678ebe03</citedby><cites>FETCH-LOGICAL-c390t-a86247fcc89597f0a9e1c98d904a3e70507727b5a92d200cfceb3a150678ebe03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0304383517307711$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29222038$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Wei</creatorcontrib><creatorcontrib>Liu, Yingying</creatorcontrib><creatorcontrib>Gao, Ruoling</creatorcontrib><creatorcontrib>Yu, Hongquan</creatorcontrib><creatorcontrib>Sun, Ting</creatorcontrib><title>HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on stemness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSCs comparing to non-stem tumor cells. Inhibiting HDAC6 downregulated glioma-associated oncogene homolog 1 (Gli1), Patched (Ptch1 and Ptch2) receptors, components of SHH signal, expression and activity in GSCs. Restraining HDAC6 decreased cell proliferation, induces differentiation and increased apoptosis of GSCs via inactivation of SHH/Gli1 signaling pathway. Moreover, HDAC6 inhibition decreased DNA damage repair capacity of GSCs through degradation of checkpoint kinase (CHK) 1 caused by X-linked inhibitor of apoptosis (XIAP) downregulation, leading to elevated radiosensitivity. Taken together, these findings indicate that HDAC6 inhibition decreased stemness of GSCs and enhanced GSCs radiosensitivity through inactivating SHH/Gli1 pathway. This provides a promising novel drug target to overcome GSCs stemness and radioresistance.
•HDAC6i decreased stemness of GSCs.•HDAC6i enhanced GSCs radiosensitivity via inactivating SHH/Gli1 pathway.•HDAC6i decreased DDR of GSCs via CHK1/XIAP pathway.</description><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Brain cancer</subject><subject>Brain tumors</subject><subject>Cancer therapies</subject><subject>Cell culture</subject><subject>Cell proliferation</subject><subject>Chemotherapy</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Epidermal growth factor</subject><subject>Gli1</subject><subject>Glioblastoma</subject><subject>Glioma</subject><subject>Glioma cells</subject><subject>Gloima stem cells</subject><subject>HDAC6</subject><subject>Hedgehog pathway</subject><subject>Histone deacetylase</subject><subject>Homology</subject><subject>Inactivation</subject><subject>Inhibition</subject><subject>Inhibitor drugs</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Patients</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Radiation</subject><subject>Radiation therapy</subject><subject>Radioresistance</subject><subject>Radiosensitivity</subject><subject>Signal transduction</subject><subject>Stem cells</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>XIAP protein</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9kc-O0zAQxiMEYsvCGyBkiQuXZMfOH9sXpFWBLdJKHICz5TiTxlXiFNvZVR-Cd8ahhQMHTmNpfvPN-Puy7DWFggJtbg6F0W7EWDCgvKCsAKifZBsqOMu5FPA020AJVV6Ksr7KXoRwgERUvH6eXTHJGINSbLKfuw-324ZYN9jWRju79OwWg4HsRztPmoSIEzE4joF0tu_Ro4tW_ya16wi6QbsVX5Fl1J543V36AV1Img82nkgc_Lzsh1SRfN3tbu5GS0mwe6dH6_bkqOPwqE8vs2e9HgO-utTr7Punj9-2u_z-y93n7e19bkoJMdeiYRXvjRGylrwHLZEaKToJlS6RQw2cM97WWrKOAZjeYFtqWkPDBbYI5XX27qx79POPBUNUkw3rD7TDeQmKSl4n86igCX37D3qYF5_OXilRN03D2EpVZ8r4OQSPvTp6O2l_UhTUGpc6qHNcao1LUaZSGGnszUV8aSfs_g79yScB788AJjceLHoVjMVkeGc9mqi62f5_wy9mwalk</recordid><startdate>20180228</startdate><enddate>20180228</enddate><creator>Yang, Wei</creator><creator>Liu, Yingying</creator><creator>Gao, Ruoling</creator><creator>Yu, Hongquan</creator><creator>Sun, Ting</creator><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20180228</creationdate><title>HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway</title><author>Yang, Wei ; Liu, Yingying ; Gao, Ruoling ; Yu, Hongquan ; Sun, Ting</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-a86247fcc89597f0a9e1c98d904a3e70507727b5a92d200cfceb3a150678ebe03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Brain cancer</topic><topic>Brain tumors</topic><topic>Cancer therapies</topic><topic>Cell culture</topic><topic>Cell proliferation</topic><topic>Chemotherapy</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Epidermal growth factor</topic><topic>Gli1</topic><topic>Glioblastoma</topic><topic>Glioma</topic><topic>Glioma cells</topic><topic>Gloima stem cells</topic><topic>HDAC6</topic><topic>Hedgehog pathway</topic><topic>Histone deacetylase</topic><topic>Homology</topic><topic>Inactivation</topic><topic>Inhibition</topic><topic>Inhibitor drugs</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Patients</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Radiation</topic><topic>Radiation therapy</topic><topic>Radioresistance</topic><topic>Radiosensitivity</topic><topic>Signal transduction</topic><topic>Stem cells</topic><topic>Tumor cells</topic><topic>Tumors</topic><topic>XIAP protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Wei</creatorcontrib><creatorcontrib>Liu, Yingying</creatorcontrib><creatorcontrib>Gao, Ruoling</creatorcontrib><creatorcontrib>Yu, Hongquan</creatorcontrib><creatorcontrib>Sun, Ting</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Wei</au><au>Liu, Yingying</au><au>Gao, Ruoling</au><au>Yu, Hongquan</au><au>Sun, Ting</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2018-02-28</date><risdate>2018</risdate><volume>415</volume><spage>164</spage><epage>176</epage><pages>164-176</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on stemness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSCs comparing to non-stem tumor cells. Inhibiting HDAC6 downregulated glioma-associated oncogene homolog 1 (Gli1), Patched (Ptch1 and Ptch2) receptors, components of SHH signal, expression and activity in GSCs. Restraining HDAC6 decreased cell proliferation, induces differentiation and increased apoptosis of GSCs via inactivation of SHH/Gli1 signaling pathway. Moreover, HDAC6 inhibition decreased DNA damage repair capacity of GSCs through degradation of checkpoint kinase (CHK) 1 caused by X-linked inhibitor of apoptosis (XIAP) downregulation, leading to elevated radiosensitivity. Taken together, these findings indicate that HDAC6 inhibition decreased stemness of GSCs and enhanced GSCs radiosensitivity through inactivating SHH/Gli1 pathway. This provides a promising novel drug target to overcome GSCs stemness and radioresistance.
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| ispartof | Cancer letters, 2018-02, Vol.415, p.164-176 |
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| subjects | Apoptosis Autophagy Brain cancer Brain tumors Cancer therapies Cell culture Cell proliferation Chemotherapy Deoxyribonucleic acid DNA DNA damage DNA repair Epidermal growth factor Gli1 Glioblastoma Glioma Glioma cells Gloima stem cells HDAC6 Hedgehog pathway Histone deacetylase Homology Inactivation Inhibition Inhibitor drugs Kinases Laboratories Patients Protein expression Proteins Radiation Radiation therapy Radioresistance Radiosensitivity Signal transduction Stem cells Tumor cells Tumors XIAP protein |
| title | HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway |
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