An Axis between the Long Non-Coding RNA HOXA11-AS and NQOs Enhances Metastatic Ability in Oral Squamous Cell Carcinoma
Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC...
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| Veröffentlicht in: | International journal of molecular sciences 2022-09, Vol.23 (18), p.10704 |
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| creator | Nakashima, Chie Fujiwara-Tani, Rina Mori, Shiori Kishi, Shingo Ohmori, Hitoshi Fujii, Kiyomu Mori, Takuya Miyagawa, Yoshihiro Yamamoto, Kazuhiko Kirita, Tadaaki Luo, Yi Kuniyasu, Hiroki |
| description | Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2. |
| doi_str_mv | 10.3390/ijms231810704 |
| format | Article |
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HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms231810704</identifier><identifier>PMID: 36142607</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Adenine ; Animal models ; Antisense RNA ; Antisense therapy ; Apoptosis ; Cancer therapies ; Cell growth ; Colon ; Colon cancer ; Colorectal cancer ; Drug resistance ; Enzymatic activity ; Enzymes ; Fermentation ; Flavin ; Flavin-adenine dinucleotide ; Genes ; Glyceraldehyde-3-phosphate dehydrogenase ; Glycolysis ; Homeobox ; Homology ; Kinases ; Lactic acid ; Lymph nodes ; Lymphatic system ; Malic enzyme ; Medical prognosis ; Metastases ; Metastasis ; Methylation ; miRNA ; Nicotinamide ; Non-coding RNA ; Oral cancer ; Oral carcinoma ; Oral squamous cell carcinoma ; Oxidative stress ; Quinone oxidoreductase ; Quinones ; Roles ; Squamous cell carcinoma ; Tumors</subject><ispartof>International journal of molecular sciences, 2022-09, Vol.23 (18), p.10704</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c458t-30f838381f46a696ffba58c5bd454b9c9e2161332dd6922365383af625d9a3703</citedby><cites>FETCH-LOGICAL-c458t-30f838381f46a696ffba58c5bd454b9c9e2161332dd6922365383af625d9a3703</cites><orcidid>0000-0002-6900-0397 ; 0000-0003-2298-8825</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506332/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506332/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Nakashima, Chie</creatorcontrib><creatorcontrib>Fujiwara-Tani, Rina</creatorcontrib><creatorcontrib>Mori, Shiori</creatorcontrib><creatorcontrib>Kishi, Shingo</creatorcontrib><creatorcontrib>Ohmori, Hitoshi</creatorcontrib><creatorcontrib>Fujii, Kiyomu</creatorcontrib><creatorcontrib>Mori, Takuya</creatorcontrib><creatorcontrib>Miyagawa, Yoshihiro</creatorcontrib><creatorcontrib>Yamamoto, Kazuhiko</creatorcontrib><creatorcontrib>Kirita, Tadaaki</creatorcontrib><creatorcontrib>Luo, Yi</creatorcontrib><creatorcontrib>Kuniyasu, Hiroki</creatorcontrib><title>An Axis between the Long Non-Coding RNA HOXA11-AS and NQOs Enhances Metastatic Ability in Oral Squamous Cell Carcinoma</title><title>International journal of molecular sciences</title><description>Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2.</description><subject>Adenine</subject><subject>Animal models</subject><subject>Antisense RNA</subject><subject>Antisense therapy</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Cell growth</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Colorectal cancer</subject><subject>Drug resistance</subject><subject>Enzymatic activity</subject><subject>Enzymes</subject><subject>Fermentation</subject><subject>Flavin</subject><subject>Flavin-adenine dinucleotide</subject><subject>Genes</subject><subject>Glyceraldehyde-3-phosphate dehydrogenase</subject><subject>Glycolysis</subject><subject>Homeobox</subject><subject>Homology</subject><subject>Kinases</subject><subject>Lactic acid</subject><subject>Lymph nodes</subject><subject>Lymphatic system</subject><subject>Malic enzyme</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Methylation</subject><subject>miRNA</subject><subject>Nicotinamide</subject><subject>Non-coding RNA</subject><subject>Oral cancer</subject><subject>Oral carcinoma</subject><subject>Oral squamous cell carcinoma</subject><subject>Oxidative stress</subject><subject>Quinone oxidoreductase</subject><subject>Quinones</subject><subject>Roles</subject><subject>Squamous cell 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sciences</jtitle><date>2022-09-14</date><risdate>2022</risdate><volume>23</volume><issue>18</issue><spage>10704</spage><pages>10704-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>36142607</pmid><doi>10.3390/ijms231810704</doi><orcidid>https://orcid.org/0000-0002-6900-0397</orcidid><orcidid>https://orcid.org/0000-0003-2298-8825</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2022-09, Vol.23 (18), p.10704 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adenine Animal models Antisense RNA Antisense therapy Apoptosis Cancer therapies Cell growth Colon Colon cancer Colorectal cancer Drug resistance Enzymatic activity Enzymes Fermentation Flavin Flavin-adenine dinucleotide Genes Glyceraldehyde-3-phosphate dehydrogenase Glycolysis Homeobox Homology Kinases Lactic acid Lymph nodes Lymphatic system Malic enzyme Medical prognosis Metastases Metastasis Methylation miRNA Nicotinamide Non-coding RNA Oral cancer Oral carcinoma Oral squamous cell carcinoma Oxidative stress Quinone oxidoreductase Quinones Roles Squamous cell carcinoma Tumors |
| title | An Axis between the Long Non-Coding RNA HOXA11-AS and NQOs Enhances Metastatic Ability in Oral Squamous Cell Carcinoma |
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