USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer

Robyn Laura Kosinsky, Marlena Helms, Maria Zerche, Luisa Wohn, Anna Dyas, Evangelos Prokakis, Zahra Basir Kazerouni, Upasana Bedi, Florian Wegwitz, Steven A. Johnsen

Research output: Contribution to journalArticle

Abstract

As a member of the 11-gene “death-from-cancer” gene expression signature, overexpression of the Ubiquitin-Specific Protease 22 (USP22) was associated with poor prognosis in various human malignancies. To investigate the function of USP22 in cancer development and progression, we sought to detect common USP22-dependent molecular mechanisms in human colorectal and breast cancer cell lines. We performed mRNA-seq to compare gene expression profiles of various colorectal (SW837, SW480, HCT116) and mammary (HCC1954 and MCF10A) cell lines upon siRNA-mediated knockdown of USP22. Intriguingly, while USP22 depletion had highly heterogeneous effects across the cell lines, all cell lines displayed a common reduction in the expression of Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1). The downregulation of HSP90AB1 was confirmed at the protein level in these cell lines as well as in colorectal and mammary tumors in mice with tissue-specific Usp22 deletions. Mechanistically, we detected a significant reduction of H3K9ac on the HSP90AB1 gene in USP22-deficient cells. Interestingly, USP22-deficient cells displayed a high dependence on HSP90AB1 expression and diminishing HSP90 activity further using the HSP90 inhibitor Ganetespib resulted in increased therapeutic vulnerability in both colorectal and breast cancer cells in vitro. Accordingly, subcutaneously transplanted CRC cells deficient in USP22 expression displayed increased sensitivity towards Ganetespib treatment in vivo. Together, we discovered that HSP90AB1 is USP22-dependent and that cooperative targeting of USP22 and HSP90 may provide an effective approach to the treatment of colorectal and breast cancer.

Original languageEnglish (US)
Article number911
JournalCell Death and Disease
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2019

Fingerprint

Ubiquitin-Specific Proteases
HSP90 Heat-Shock Proteins
Colorectal Neoplasms
Breast Neoplasms
Cell Line
Transcriptome
Neoplasm Genes
Small Interfering RNA
Genes
Neoplasms
Breast
Down-Regulation

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer. / Kosinsky, Robyn Laura; Helms, Marlena; Zerche, Maria; Wohn, Luisa; Dyas, Anna; Prokakis, Evangelos; Kazerouni, Zahra Basir; Bedi, Upasana; Wegwitz, Florian; Johnsen, Steven A.

In: Cell Death and Disease, Vol. 10, No. 12, 911, 01.12.2019.

Research output: Contribution to journalArticle

Kosinsky, RL, Helms, M, Zerche, M, Wohn, L, Dyas, A, Prokakis, E, Kazerouni, ZB, Bedi, U, Wegwitz, F & Johnsen, SA 2019, 'USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer', Cell Death and Disease, vol. 10, no. 12, 911. https://doi.org/10.1038/s41419-019-2141-9
Kosinsky, Robyn Laura ; Helms, Marlena ; Zerche, Maria ; Wohn, Luisa ; Dyas, Anna ; Prokakis, Evangelos ; Kazerouni, Zahra Basir ; Bedi, Upasana ; Wegwitz, Florian ; Johnsen, Steven A. / USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer. In: Cell Death and Disease. 2019 ; Vol. 10, No. 12.
@article{3a71aaaf497a45edb531203472f13406,
title = "USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer",
abstract = "As a member of the 11-gene “death-from-cancer” gene expression signature, overexpression of the Ubiquitin-Specific Protease 22 (USP22) was associated with poor prognosis in various human malignancies. To investigate the function of USP22 in cancer development and progression, we sought to detect common USP22-dependent molecular mechanisms in human colorectal and breast cancer cell lines. We performed mRNA-seq to compare gene expression profiles of various colorectal (SW837, SW480, HCT116) and mammary (HCC1954 and MCF10A) cell lines upon siRNA-mediated knockdown of USP22. Intriguingly, while USP22 depletion had highly heterogeneous effects across the cell lines, all cell lines displayed a common reduction in the expression of Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1). The downregulation of HSP90AB1 was confirmed at the protein level in these cell lines as well as in colorectal and mammary tumors in mice with tissue-specific Usp22 deletions. Mechanistically, we detected a significant reduction of H3K9ac on the HSP90AB1 gene in USP22-deficient cells. Interestingly, USP22-deficient cells displayed a high dependence on HSP90AB1 expression and diminishing HSP90 activity further using the HSP90 inhibitor Ganetespib resulted in increased therapeutic vulnerability in both colorectal and breast cancer cells in vitro. Accordingly, subcutaneously transplanted CRC cells deficient in USP22 expression displayed increased sensitivity towards Ganetespib treatment in vivo. Together, we discovered that HSP90AB1 is USP22-dependent and that cooperative targeting of USP22 and HSP90 may provide an effective approach to the treatment of colorectal and breast cancer.",
author = "Kosinsky, {Robyn Laura} and Marlena Helms and Maria Zerche and Luisa Wohn and Anna Dyas and Evangelos Prokakis and Kazerouni, {Zahra Basir} and Upasana Bedi and Florian Wegwitz and Johnsen, {Steven A.}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41419-019-2141-9",
language = "English (US)",
volume = "10",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer

AU - Kosinsky, Robyn Laura

AU - Helms, Marlena

AU - Zerche, Maria

AU - Wohn, Luisa

AU - Dyas, Anna

AU - Prokakis, Evangelos

AU - Kazerouni, Zahra Basir

AU - Bedi, Upasana

AU - Wegwitz, Florian

AU - Johnsen, Steven A.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - As a member of the 11-gene “death-from-cancer” gene expression signature, overexpression of the Ubiquitin-Specific Protease 22 (USP22) was associated with poor prognosis in various human malignancies. To investigate the function of USP22 in cancer development and progression, we sought to detect common USP22-dependent molecular mechanisms in human colorectal and breast cancer cell lines. We performed mRNA-seq to compare gene expression profiles of various colorectal (SW837, SW480, HCT116) and mammary (HCC1954 and MCF10A) cell lines upon siRNA-mediated knockdown of USP22. Intriguingly, while USP22 depletion had highly heterogeneous effects across the cell lines, all cell lines displayed a common reduction in the expression of Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1). The downregulation of HSP90AB1 was confirmed at the protein level in these cell lines as well as in colorectal and mammary tumors in mice with tissue-specific Usp22 deletions. Mechanistically, we detected a significant reduction of H3K9ac on the HSP90AB1 gene in USP22-deficient cells. Interestingly, USP22-deficient cells displayed a high dependence on HSP90AB1 expression and diminishing HSP90 activity further using the HSP90 inhibitor Ganetespib resulted in increased therapeutic vulnerability in both colorectal and breast cancer cells in vitro. Accordingly, subcutaneously transplanted CRC cells deficient in USP22 expression displayed increased sensitivity towards Ganetespib treatment in vivo. Together, we discovered that HSP90AB1 is USP22-dependent and that cooperative targeting of USP22 and HSP90 may provide an effective approach to the treatment of colorectal and breast cancer.

AB - As a member of the 11-gene “death-from-cancer” gene expression signature, overexpression of the Ubiquitin-Specific Protease 22 (USP22) was associated with poor prognosis in various human malignancies. To investigate the function of USP22 in cancer development and progression, we sought to detect common USP22-dependent molecular mechanisms in human colorectal and breast cancer cell lines. We performed mRNA-seq to compare gene expression profiles of various colorectal (SW837, SW480, HCT116) and mammary (HCC1954 and MCF10A) cell lines upon siRNA-mediated knockdown of USP22. Intriguingly, while USP22 depletion had highly heterogeneous effects across the cell lines, all cell lines displayed a common reduction in the expression of Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1). The downregulation of HSP90AB1 was confirmed at the protein level in these cell lines as well as in colorectal and mammary tumors in mice with tissue-specific Usp22 deletions. Mechanistically, we detected a significant reduction of H3K9ac on the HSP90AB1 gene in USP22-deficient cells. Interestingly, USP22-deficient cells displayed a high dependence on HSP90AB1 expression and diminishing HSP90 activity further using the HSP90 inhibitor Ganetespib resulted in increased therapeutic vulnerability in both colorectal and breast cancer cells in vitro. Accordingly, subcutaneously transplanted CRC cells deficient in USP22 expression displayed increased sensitivity towards Ganetespib treatment in vivo. Together, we discovered that HSP90AB1 is USP22-dependent and that cooperative targeting of USP22 and HSP90 may provide an effective approach to the treatment of colorectal and breast cancer.

UR - http://www.scopus.com/inward/record.url?scp=85076013448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076013448&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-2141-9

DO - 10.1038/s41419-019-2141-9

M3 - Article

C2 - 31801945

AN - SCOPUS:85076013448

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 12

M1 - 911

ER -