PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair.
PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair.
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DOI：
10.1038/s41419-022-05402-7
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发表时间：
2022-11-19
影响因子：
9
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Yu, Yue;Liu, Tingting;Yu, Guanyu;Wang, Hang;Du, Zhipeng;Chen, Yuanyuan;Yang, Nan;Cao, Kun;Liu, Chunlei;Wan, Zhijie;Shen, Hui;Gao, Fu;Yang, Yanyong;Zhang, Wei
新辅助放疗是局部晚期直肠癌的标准治疗方法，然而，对放化疗的耐药性是改善治疗效果的主要障碍之一。本研究的目的是探讨PRDM15在结直肠癌放射耐药中的作用，并阐明其潜在机制。在本研究中，我们证明了DNA损伤后，PRDM15上调并定位于DNA损伤位点，与γ-H2AX共定位。敲低PRDM15抑制结直肠癌细胞的DNA损伤修复并增加放射敏感性。机制上，PRDM15通过与DNA- pkcs和Ku70/Ku80复合体相互作用促进DNA修复。在直肠癌临床前模型中，敲低PRDM15使细胞源异种移植物和患者源异种移植物对放疗敏感。在80例接受新辅助放化疗的直肠癌患者中，PRDM15表达越高，肿瘤消退越弱，预后越差。我们的研究结果表明，抑制PRDM15可以通过取消结直肠癌细胞的DNA修复来有效克服辐射耐药。此外，PRDM15的表达水平可用于预测直肠癌患者的放疗反应性和新辅助放疗的预后。
Neoadjuvant radiotherapy is a standard treatment for locally advanced rectal cancer, however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to explore the role of PRDM15 involved in the radioresistance of colorectal cancer and to clarify the underlying mechanism. In present study, we demonstrated that, after DNA damage, PRDM15 was upregulated and localized to DNA damage sites, co-localizing with γ-H2AX. Knockdown of PRDM15 inhibited DNA damage repair and increased radiosensitivity in colorectal cancer cells. Mechanistically, PRDM15 promoted DNA repair by interacting with DNA-PKcs and Ku70/Ku80 complex. In preclinical models of rectal cancer, knockdown of PRDM15 sensitized cell derived xenograft and patient derived xenograft to radiotherapy. In 80 rectal cancer patients treated with neoadjuvant chemoradiotherapy, higher PRDM15 expression was observed associated with weaker tumor regression and poorer prognosis. Our findings revealed that inhibiting PRDM15 was potent to overcome radioresistance through abrogating DNA repair in colorectal cancer cells. Additionally, the expression level of PRDM15 could be applied to predict radiotherapy responsiveness and the outcome of neoadjuvant radiotherapy in rectal cancer patients.
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影响因子：
16.8
作者：
Leitch, Harry G.;McEwen, Kirsten R.;Turp, Aleksandra;Encheva, Vesela;Carroll, Tom;Grabole, Nils;Mansfield, William;Nashun, Buhe;Knezovich, Jaysen G.;Smith, Austin;Surani, M. Azim;Hajkova, Petra
通讯作者：
Hajkova, Petra
影响因子：
4.8
作者：
Jack, MT;Woo, RA;Lee, PWK
通讯作者：
Lee, PWK
影响因子：
158.5
作者：
Kapiteijn, E;Marijnen, CAM;van de Velde, CJH
通讯作者：
van de Velde, CJH
影响因子：
120.7
作者：
Cammà, C;Giunta, M;Cottone, M
通讯作者：
Cottone, M
影响因子：
50.3
作者：
Li, Chen;Sun, Yi-Di;Zeng, Rong
通讯作者：
Zeng, Rong