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WDHD1 is essential for the survival of PTEN-inactive triple negative breast cancer

WDHD1 is essential for the survival of PTEN-inactive triple negative breast cancer
WDHD1 is essential for the survival of PTEN-inactive triple negative breast cancer
Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, making it difficult to target therapeutically. Targeting synthetic lethality is an alternative approach for cancer treatment. TNBC shows frequent loss of phosphatase and tensin homolog (PTEN) expression, which is associated with poor prognosis and treatment response. To identify PTEN synthetic lethal interactions, TCGA analysis coupled with a whole genome siRNA screen in isogenic PTEN negative and positive cells were performed. Among the candidate genes essential for the survival of PTEN-inactive TNBC cells, WDHD1 (WD repeat and high-mobility group box DNA binding protein 1) expression was increased in the low vs. high PTEN TNBC samples. It was also the top hit in the siRNA screen and its knockdown significantly inhibited cell viability in PTEN negative cells, which was further validated in 2D and 3D cultures. Mechanistically, WDHD1 is important to mediate a high demand of protein translation in PTEN-inactive TNBC. Finally, the importance of WDHD1 in TNBC was confirmed in patient samples obtained from the TCGA and tissue microarrays with clinic-pathological information. Taken together, as an essential gene for the survival of PTEN-inactive TNBC cells, WDHD1 could be a potential biomarker or a therapeutic target for TNBC
2041-4889
Ertay, Ayse
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Liu, Huiquan
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Liu, Dian
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Peng, Ping
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Hill, Charlotte
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Xiong, Hua
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Hancock, David
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Yuan, Xianglin
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Przewloka, Marcin
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Coldwell, Mark
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Howell, Michael
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Skipp, Paul
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Ewing, Robert
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Downward, Julian
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Wang, Yihua
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Ertay, Ayse
fdd0c5cb-cfb2-4e25-9343-cdc462035531
Liu, Huiquan
e477dc1a-5f4d-4c8d-8f8e-34f6092afbb9
Liu, Dian
ce4bfe26-a6f6-48fa-a102-918fddbb464e
Peng, Ping
7618ff50-141c-4624-a765-b3e82fa93dd3
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Xiong, Hua
1def5ef5-af28-47f6-ae85-22977633a75d
Hancock, David
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Yuan, Xianglin
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Przewloka, Marcin
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Coldwell, Mark
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Howell, Michael
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Skipp, Paul
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Ewing, Robert
022c5b04-da20-4e55-8088-44d0dc9935ae
Downward, Julian
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Wang, Yihua
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Ertay, Ayse, Liu, Huiquan, Liu, Dian, Peng, Ping, Hill, Charlotte, Xiong, Hua, Hancock, David, Yuan, Xianglin, Przewloka, Marcin, Coldwell, Mark, Howell, Michael, Skipp, Paul, Ewing, Robert, Downward, Julian and Wang, Yihua (2020) WDHD1 is essential for the survival of PTEN-inactive triple negative breast cancer. Cell Death and Disease, [1001]. (doi:10.1038/s41419-020-03210-5).

Record type: Article

Abstract

Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, making it difficult to target therapeutically. Targeting synthetic lethality is an alternative approach for cancer treatment. TNBC shows frequent loss of phosphatase and tensin homolog (PTEN) expression, which is associated with poor prognosis and treatment response. To identify PTEN synthetic lethal interactions, TCGA analysis coupled with a whole genome siRNA screen in isogenic PTEN negative and positive cells were performed. Among the candidate genes essential for the survival of PTEN-inactive TNBC cells, WDHD1 (WD repeat and high-mobility group box DNA binding protein 1) expression was increased in the low vs. high PTEN TNBC samples. It was also the top hit in the siRNA screen and its knockdown significantly inhibited cell viability in PTEN negative cells, which was further validated in 2D and 3D cultures. Mechanistically, WDHD1 is important to mediate a high demand of protein translation in PTEN-inactive TNBC. Finally, the importance of WDHD1 in TNBC was confirmed in patient samples obtained from the TCGA and tissue microarrays with clinic-pathological information. Taken together, as an essential gene for the survival of PTEN-inactive TNBC cells, WDHD1 could be a potential biomarker or a therapeutic target for TNBC

Text
WDHD1 in TNBC - Accepted Manuscript
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Accepted/In Press date: 5 November 2020
e-pub ahead of print date: 21 November 2020

Identifiers

Local EPrints ID: 444808
URI: http://eprints.soton.ac.uk/id/eprint/444808
ISSN: 2041-4889
PURE UUID: 43810c9f-c198-43c3-9355-817dd88b2a71
ORCID for Marcin Przewloka: ORCID iD orcid.org/0000-0002-0329-9162
ORCID for Mark Coldwell: ORCID iD orcid.org/0000-0002-6243-3886
ORCID for Paul Skipp: ORCID iD orcid.org/0000-0002-2995-2959
ORCID for Robert Ewing: ORCID iD orcid.org/0000-0001-6510-4001
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 05 Nov 2020 17:31
Last modified: 12 Mar 2021 05:01

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