RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis
Abstract RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs and their partners, which may potentially serve as the cancer therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing p...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-07-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01033-8 |
| _version_ | 1828260085766291456 |
|---|---|
| author | Ha Zhu Kun Chen Yali Chen Juan Liu Xiaomin Zhang Yumei Zhou Qiuyan Liu Bingjing Wang Taoyong Chen Xuetao Cao |
| author_facet | Ha Zhu Kun Chen Yali Chen Juan Liu Xiaomin Zhang Yumei Zhou Qiuyan Liu Bingjing Wang Taoyong Chen Xuetao Cao |
| author_sort | Ha Zhu |
| collection | DOAJ |
| description | Abstract RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs and their partners, which may potentially serve as the cancer therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing protein 4 (ZCCHC4) is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma (HCC), pancreatic cancer and colon cancer. ZCCHC4 promotes chemoresistance of HCC cells to DNA-damage agent (DDA) both in vitro and in vivo. HCC cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDA-induced antitumor effect. Mechanistically, ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA (lncRNA) AL133467.2 to hamper its pro-apoptotic function. Also, ZCCHC4 blocks the interaction between AL133467.2 and γH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to DDAs. Knockout of ZCCHC4 promotes AL133467.2 and γH2AX interaction for enhancing chemosensitivity in HCC cells. Together, our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects, providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance. |
| first_indexed | 2024-04-13T03:18:14Z |
| format | Article |
| id | doaj.art-2808e379e9254c02b4c3826e53aaf9f4 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-13T03:18:14Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-2808e379e9254c02b4c3826e53aaf9f42022-12-22T03:04:50ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352022-07-017111310.1038/s41392-022-01033-8RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosisHa Zhu0Kun Chen1Yali Chen2Juan Liu3Xiaomin Zhang4Yumei Zhou5Qiuyan Liu6Bingjing Wang7Taoyong Chen8Xuetao Cao9National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical UniversityDepartment of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesNational Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical UniversityDepartment of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesNational Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical UniversityDepartment of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesNational Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical UniversityAbstract RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs and their partners, which may potentially serve as the cancer therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing protein 4 (ZCCHC4) is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma (HCC), pancreatic cancer and colon cancer. ZCCHC4 promotes chemoresistance of HCC cells to DNA-damage agent (DDA) both in vitro and in vivo. HCC cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDA-induced antitumor effect. Mechanistically, ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA (lncRNA) AL133467.2 to hamper its pro-apoptotic function. Also, ZCCHC4 blocks the interaction between AL133467.2 and γH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to DDAs. Knockout of ZCCHC4 promotes AL133467.2 and γH2AX interaction for enhancing chemosensitivity in HCC cells. Together, our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects, providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance.https://doi.org/10.1038/s41392-022-01033-8 |
| spellingShingle | Ha Zhu Kun Chen Yali Chen Juan Liu Xiaomin Zhang Yumei Zhou Qiuyan Liu Bingjing Wang Taoyong Chen Xuetao Cao RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis Signal Transduction and Targeted Therapy |
| title | RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis |
| title_full | RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis |
| title_fullStr | RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis |
| title_full_unstemmed | RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis |
| title_short | RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis |
| title_sort | rna binding protein zcchc4 promotes human cancer chemoresistance by disrupting dna damage induced apoptosis |
| url | https://doi.org/10.1038/s41392-022-01033-8 |
| work_keys_str_mv | AT hazhu rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT kunchen rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT yalichen rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT juanliu rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT xiaominzhang rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT yumeizhou rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT qiuyanliu rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT bingjingwang rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT taoyongchen rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis AT xuetaocao rnabindingproteinzcchc4promoteshumancancerchemoresistancebydisruptingdnadamageinducedapoptosis |