PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib
Abstract As a chromatin remodelling factor, high mobility group A1 (HMGA1) plays various roles in both physiological and pathological conditions. However, its role in DNA damage response and DNA damage‐based chemotherapy remains largely unexplored. In this study, we report the poly ADP‐ribosylation...
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70111 |
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| author | Xin‐Yuan Lei Kai‐Yue He Qiu‐Tong Li Lei Zhang Dan‐Hui Wu Jing‐Yu Yang Jin‐Rong Guo Meng‐Jie Liu Zi‐Long Zhao Jun‐Qi Li Huai Liu Yuan Zhao Yu‐Jia Li Qian‐Hui Sun Chen‐Guang Wu Yun‐Fan Wang Geng‐Sheng Cao Gang Wang Yong‐Ping Jian Zhi‐Xiang Xu |
| author_facet | Xin‐Yuan Lei Kai‐Yue He Qiu‐Tong Li Lei Zhang Dan‐Hui Wu Jing‐Yu Yang Jin‐Rong Guo Meng‐Jie Liu Zi‐Long Zhao Jun‐Qi Li Huai Liu Yuan Zhao Yu‐Jia Li Qian‐Hui Sun Chen‐Guang Wu Yun‐Fan Wang Geng‐Sheng Cao Gang Wang Yong‐Ping Jian Zhi‐Xiang Xu |
| author_sort | Xin‐Yuan Lei |
| collection | DOAJ |
| description | Abstract As a chromatin remodelling factor, high mobility group A1 (HMGA1) plays various roles in both physiological and pathological conditions. However, its role in DNA damage response and DNA damage‐based chemotherapy remains largely unexplored. In this study, we report the poly ADP‐ribosylation (PARylation) of HMGA1 during DNA damage, leading to desensitization of esophageal squamous cell carcinoma (ESCC) cells to the poly(ADP‐ribose) polymerase 1 (PARP1) inhibitor, olaparib. We found that HMGA1 accumulates at sites of DNA damage, where it interacts with PARP1 and undergoes PARylation at residues E47 and E50 in its conserved AT‐hook domain. This modification enhances the accumulation of Ku70/Ku80 at the site of DNA damage and activates the DNA‐dependent protein kinase catalytic subunit, facilitating nonhomologous end‐joining repair. In both subcutaneous tumour models and genetically engineered mouse models of in situ esophageal cancer, HMGA1 interference increased tumour sensitivity to olaparib. Moreover, HMGA1 was highly expressed in ESCC tissues and positively correlated with PARP1 levels as well as poor prognosis in ESCC patients. Taken together, these findings reveal a mechanistic link between HMGA1 and PARP1 in regulating cell responses to DNA damage and suggest that targeting HMGA1 could be a promising strategy to increase cancer cell sensitivity to olaparib. |
| format | Article |
| id | doaj-art-0acc00287dce43fd9ae284bc44625acb |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-0acc00287dce43fd9ae284bc44625acb2025-01-30T03:56:55ZengWileyClinical and Translational Medicine2001-13262024-12-011412n/an/a10.1002/ctm2.70111PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparibXin‐Yuan Lei0Kai‐Yue He1Qiu‐Tong Li2Lei Zhang3Dan‐Hui Wu4Jing‐Yu Yang5Jin‐Rong Guo6Meng‐Jie Liu7Zi‐Long Zhao8Jun‐Qi Li9Huai Liu10Yuan Zhao11Yu‐Jia Li12Qian‐Hui Sun13Chen‐Guang Wu14Yun‐Fan Wang15Geng‐Sheng Cao16Gang Wang17Yong‐Ping Jian18Zhi‐Xiang Xu19School of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaSchool of Life Sciences Henan University Kaifeng ChinaAbstract As a chromatin remodelling factor, high mobility group A1 (HMGA1) plays various roles in both physiological and pathological conditions. However, its role in DNA damage response and DNA damage‐based chemotherapy remains largely unexplored. In this study, we report the poly ADP‐ribosylation (PARylation) of HMGA1 during DNA damage, leading to desensitization of esophageal squamous cell carcinoma (ESCC) cells to the poly(ADP‐ribose) polymerase 1 (PARP1) inhibitor, olaparib. We found that HMGA1 accumulates at sites of DNA damage, where it interacts with PARP1 and undergoes PARylation at residues E47 and E50 in its conserved AT‐hook domain. This modification enhances the accumulation of Ku70/Ku80 at the site of DNA damage and activates the DNA‐dependent protein kinase catalytic subunit, facilitating nonhomologous end‐joining repair. In both subcutaneous tumour models and genetically engineered mouse models of in situ esophageal cancer, HMGA1 interference increased tumour sensitivity to olaparib. Moreover, HMGA1 was highly expressed in ESCC tissues and positively correlated with PARP1 levels as well as poor prognosis in ESCC patients. Taken together, these findings reveal a mechanistic link between HMGA1 and PARP1 in regulating cell responses to DNA damage and suggest that targeting HMGA1 could be a promising strategy to increase cancer cell sensitivity to olaparib.https://doi.org/10.1002/ctm2.70111chemotherapy sensitivityDNA damageESCCHMGA1OlaparibPARP1 |
| spellingShingle | Xin‐Yuan Lei Kai‐Yue He Qiu‐Tong Li Lei Zhang Dan‐Hui Wu Jing‐Yu Yang Jin‐Rong Guo Meng‐Jie Liu Zi‐Long Zhao Jun‐Qi Li Huai Liu Yuan Zhao Yu‐Jia Li Qian‐Hui Sun Chen‐Guang Wu Yun‐Fan Wang Geng‐Sheng Cao Gang Wang Yong‐Ping Jian Zhi‐Xiang Xu PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib Clinical and Translational Medicine chemotherapy sensitivity DNA damage ESCC HMGA1 Olaparib PARP1 |
| title | PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib |
| title_full | PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib |
| title_fullStr | PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib |
| title_full_unstemmed | PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib |
| title_short | PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib |
| title_sort | parylation of hmga1 desensitizes esophageal squamous cell carcinoma to olaparib |
| topic | chemotherapy sensitivity DNA damage ESCC HMGA1 Olaparib PARP1 |
| url | https://doi.org/10.1002/ctm2.70111 |
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