Targeting the HECTD3-p62 axis increases the radiosensitivity of triple negative breast cancer cells.

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-11-01 DOI:10.1038/s41420-024-02154-5

Maobo Huang, Wenjing Liu, Zhuo Cheng, Fubing Li, Yanjie Kong, Chuanyu Yang, Yu Tang, Dewei Jiang, Wenhui Li, Yudie Hu, Jinhui Hu, PemaTenzin Puno, Ceshi Chen

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Abstract

Triple negative breast cancer is the most malignant subtype of breast cancer and current treatment options are limited. Radiotherapy is one of the primary therapeutic options for patients with TNBC. In this study, we discovered that the E3 ubiquitin ligase, HECTD3, promoted TNBC cell survival after irradiation. HECTD3 collaborated with UbcH5b to promote p62 ubiquitination and autophagy while HECTD3 deletion led to p62 accumulation in the nucleus in response to irradiation, thus inhibiting RNF168 mediated DNA damage repair. Furthermore, the HECTD3/UbcH5b inhibitor, PC3-15, increased the radiosensitivity of TNBC cells by inhibiting DNA damage repair. Taken together, we conclude that HECTD3 promotes autophagy and DNA damage repair in response to irradiation in a p62-denpendent manner, and that inhibition of the HECTD3-p62 axis could be a potential therapeutic strategy for patients with TNBC in addition to radiotherapy.

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靶向 HECTD3-p62 轴可提高三阴性乳腺癌细胞的放射敏感性。

三阴性乳腺癌是恶性程度最高的乳腺癌亚型，目前的治疗方案有限。放疗是 TNBC 患者的主要治疗选择之一。在这项研究中，我们发现E3泛素连接酶HECTD3能促进TNBC细胞在照射后存活。HECTD3与UbcH5b合作促进p62泛素化和自噬，而HECTD3缺失会导致p62在辐照后在细胞核中积累，从而抑制RNF168介导的DNA损伤修复。此外，HECTD3/UbcH5b抑制剂PC3-15通过抑制DNA损伤修复增加了TNBC细胞的辐射敏感性。综上所述，我们得出结论：HECTD3以p62依赖的方式促进自噬和DNA损伤修复以应对辐照，抑制HECTD3-p62轴可能是TNBC患者放疗之外的一种潜在治疗策略。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.