The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors

Peng, Yangqin; Liao, Qingchao; Tan, Wei; Peng, Changmin; Hu, Zhaohua; Chen, Yali; Li, Zhuqing; Li, Jing; Zhen, Bei; Zhu, Wenge; Li, Xiangpan; Yao, Yi; Song, Qibin; Liu, Chengsheng; Qi, Xiangdong; He, Fuchu; Pei, Huadong

doi:10.1038/s41467-019-09232-8

Cited by 73 publications

(69 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As it was found out, CPNE1 expression levels were higher in radioresistant patients with TNBC than radiosensitive patients with TNBC, and the cell viability was also inhibited significantly in primary isolated TNBC cells with lower CPNE1 expression after radiation therapy. Measurement of γ‐H2AX is a sensitive and specific assay for unrepaired DNA damages 26,27 . Consistent with this notion, our data show that CPNE1 knockdown promoted DNA damage‐induced γ‐H2AX foci formation in TNBC cells, while the opposite effect was demonstrated when CPNE1 was upregulated.…”

Section: Discussionsupporting

confidence: 86%

See 1 more Smart Citation

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Shao

Zhang³

et al. 2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

Elevated expression of Copine 1 (CPNE1) has been observed in multiple cancers; however, the underlying mechanisms by which it affects cancer cells are unclear. We aimed to study the effect of CPNE1 on the tumorigenesis and radioresistance of triple‐negative breast cancer (TNBC). Quantitative real‐time polymerase chain reaction was used to detect the expression of CPNE1 in TNBC tissues and cell lines. Western blot, immunohistochemistry, and immunofluorescence were used to investigate the levels of CPNE1, p‐AKT, AKT, cleaved caspase‐3, cleaved PARP1, and γ‐H2AX. Cell viability and apoptosis were measured by CCK‐8 and flow cytometry, respectively. CPNE1 was overexpressed in TNBC tissues and cell lines and was associated with tumor size, distant metastases, and survival rates of patients with TNBC. Moreover, function study shows that CPNE1 promoted cell viability and inhibited cell apoptosis in vitro and inhibited the radiosensitivity of TNBC. Importantly, inactivation of AKT signaling inhibited the tumorigenesis and radioresistance mediated by CPNE1 in TNBC cells. In vivo xenograft study also shows that CPNE1 knockdown inhibited tumor growth and promoted cell apoptosis. Overall, our findings suggest that CPNE1 promotes tumorigenesis and radioresistance in TNBC by regulating AKT activation and targeted CPNE1 expression may be a strategy to sensitize TNBC cells toward radiation therapy.

show abstract

Section: Discussionsupporting

confidence: 86%

“…Measurement of γ-H2AX is a sensitive and specific assay for unrepaired DNA damages. 26,27 Consistent with this notion, our data show that CPNE1 knockdown promoted DNA damage-induced γ-H2AX foci formation in TNBC cells, while the opposite effect was demonstrated when CPNE1 was upregulated. Compared with CPNE1 higher expressed HCC-1937…”

Section: Discussionsupporting

confidence: 84%

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Shao

Zhang³

et al. 2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…We report that spontaneous genotoxic stress and enhanced sensitivity to clastogenic agents accompanied the decrease in viability of USP15 deficient hematopoietic progenitors and leukemia cells in vitro and of mouse primitive hematopoietic progenitors in vivo. These data link USP15 to the DDR and are consistent with previous work in cancer cell lines (Fielding et al, 2018;Mu et al, 2007;Nishi et al, 2014;Peng et al, 2019). Although a genome maintenance defect may contribute to loss of fitness of USP15 deficient HSCs, understanding how USP15 modulates the damage response and how its loss precisely impacts on HSC and cancer cells maintenance will require deep molecular characterization, not least through the identification of context-specific interactors.…”

Section: Discussionsupporting

confidence: 84%

“…7H). A role for USP15 in supporting the DNA damage response was recently reported in breast cancer cells (Peng et al, 2019). In keeping with those findings, Rad51 protein levels were diminished by USP15 knockdown in MV411 and Kasumi-1 leukemia cells (Fig.…”

Section: Usp15 Loss Leads To Genome Instability In Leukemia Cell Linesupporting

confidence: 88%

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

Berk

Lancini

Serresi

et al. 2020

Preprint

View full text Add to dashboard Cite

Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo.Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells.

show abstract

“…Consequently, overexpression of USP13 renders ovarian cancer cells resistant to chemotherapeutic drug cisplatin and PARP inhibitor Olaparib . Similarly, USP15 regulates HR repair by deubiquitinating BARD1, a major BRCA1 binding partner, and decreases PARP inhibitor sensitivity in cancer cells . USP21 deubiquitinates and stabilizes BRCA2 in hepatocellular carcinoma cells to promote tumor cell growth .…”

Section: Discussionmentioning

confidence: 99%

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

Zhang

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

BRCA1, a multifunctional protein with an important role in DNA double‐strand break repair by homologous recombination (HR), is subjected to ubiquitin‐dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin‐specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small‐molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild‐type USP9X, but not its deubiquitinase activity‐defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half‐life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X‐depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA‐damaging agents.

show abstract

The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors

Cited by 73 publications

References 68 publications

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

Contact Info

Product

Resources

About