Ubiquitin-specific protease 7 downregulation suppresses breast cancer in vitro

Hayal, Taha Bartu; Doğan, Ayşegül; Şişli, Hatice Burcu; Kıratlı, Binnur; Şahın, Fikrettin

doi:10.3906/biy-1912-83

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…In addition, our data demonstrate a pivotal role of Usp7 for viability and competitive growth of breast cancer cells (Figures 4 and 6 ). In line with our data, the DUB Usp7, also known as Herpesvirus associated protease (HAUSP), is generally known to act tumor-promoting in various cancers 67 - 69 , 80 , including breast cancer 70 - 73 . Based on our results, we confirmed the tumor-promoting function of Usp7 in breast cancer.…”

Section: Discussionsupporting

confidence: 87%

“…For all 12 hits, knockdown of the respective proteases by at least one of the two tested miR-E constructs sensitized murine PyB6-TA breast cancer cells to PI3K inhibition by BKM (Supplementary Figure S2 ). Finally, we decided to further investigate Usp7, Metap1 and Metap2 due to most distinct effects in the first validation assays and literature postulating tumor-promoting functions of these proteases 62 - 73 . Metap1 and 2 (isoforms) are metalloproteases that co-translationally remove the initiator methionine from newly synthesized proteins 74 , 75 .…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, Usp7 inhibition or depletion has been shown to impair cell cycle progression and proliferation also in a p53- independent manner by regulating genome stability and repair 69 , 88 , 89 . Accordingly, pharmacological inhibition or knockdown of USP7 in human breast cancer cells with different p53 status is known to reduce cell proliferation, cell migration and colony formation 73 .…”

Section: Discussionmentioning

confidence: 99%

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RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Hölzen¹,

Mitschke²,

Schönichen³

et al. 2022

Theranostics

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Rationale: PI3K/mTOR signaling is frequently upregulated in breast cancer making inhibitors of this pathway highly promising anticancer drugs. However, PI3K-inhibitors have a low therapeutic index. Therefore, finding novel combinatory treatment options represents an important step towards clinical implementation of PI3K pathway inhibition in breast cancer therapy. Here, we propose proteases as potential synergistic partners with simultaneous PI3K inhibition in breast cancer cells. Methods: We performed mRNA expression studies and unbiased functional genetic synthetic lethality screens by a miR-E based knockdown system targeting all genome-encoded proteases, i.e. the degradome of breast cancer cells. Importantly theses RNA interference screens were done in combination with two PI3K pathway inhibitors. Protease hits were validated in human and murine breast cancer cell lines as well as in non-cancerous cells by viability and growth assays. Results: The degradome-wide genetic screens identified 181 proteases that influenced susceptibility of murine breast cancer cells to low dose PI3K inhibition. Employing independently generated inducible knockdown cell lines we validated 12 protease hits in breast cancer cells. In line with the known tumor promoting function of these proteases we demonstrated Usp7 and Metap2 to be important for murine and human breast cancer cell growth and discovered a role for Metap1 in this context. Most importantly, we demonstrated that Usp7, Metap1 or Metap2 knockdown combined with simultaneous PI3K inhibition resulted in synergistic impairment of murine and human breast cancer cell growth Conclusion: We successfully established proteases as combinatory targets with PI3K inhibition in human and murine breast cancer cells. Usp7, Metap1 and Metap2 are synthetic lethal partners of simultaneous protease/PI3K inhibition, which may refine future breast cancer therapy.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Hölzen¹,

Mitschke²,

Schönichen³

et al. 2022

Theranostics

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show abstract

“…Many DUBs are linked to cancer (34,35,46). For example, Usp7 is known to act as tumorpromoting in various cancer entities (47-50) including breast cancer (51)(52)(53). Together with the known cancer-promoting function of the UPS, the detection of many proteasomal components and DUBs as strong depletion hits proves the validity of our screening approach.…”

Section: Discussionmentioning

confidence: 85%

Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth

Hölzen

Syré²,

Mitschke³

et al. 2022

Front. Oncol.

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Proteases are known to promote or impair breast cancer progression and metastasis. However, while a small number of the 588 human and 672 murine protease genes have been extensively studied, others were neglected. For an unbiased functional analysis of all genome-encoded proteases, i.e., the degradome, in breast cancer cell growth, we applied an inducible RNA interference library for protease-focused genetic screens. Importantly, these functional screens were performed in two phenotypically different murine breast cancer cell lines, including one stem cell-like cell line that showed phenotypic plasticity under changed nutrient and oxygen availability. Our unbiased genetic screens identified 252 protease genes involved in breast cancer cell growth that were further restricted to 100 hits by a selection process. Many of those hits were supported by literature, but some proteases were novel in their functional link to breast cancer. Interestingly, we discovered that the environmental conditions influence the degree of breast cancer cell dependency on certain proteases. For example, breast cancer stem cell-like cells were less susceptible to depletion of several mitochondrial proteases in hypoxic conditions. From the 100 hits, nine proteases were functionally validated in murine breast cancer cell lines using individual knockdown constructs, highlighting the high reliability of our screens. Specifically, we focused on mitochondrial processing peptidase (MPP) subunits alpha (Pmpca) and beta (Pmpcb) and discovered that MPP depletion led to a disadvantage in cell growth, which was linked to mitochondrial dysfunction.

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“…FT827/671 inhibited tumors by degrading the oncogenic E3 ligase MDM2 ( Turnbull et al, 2017 ). In the latest study, P5091 inhibitors showed robust tumor suppression effects in preclinical models of various tumors ( An et al, 2017 ; Wang et al, 2017 ; Hayal et al, 2020 ; He et al, 2020 ; Lee et al, 2020 ). Among these cancers, in colorectal cancer, P5091 improves the antitumor immune response and reduces the proportion of Tregs in tumor xenografts in mice ( Fu et al, 2019 ).…”

Section: Research On Dub Inhibitors and Their Effects On Srss And Taimmentioning

confidence: 99%

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

Guo

Xia

Deng

et al. 2021

Front. Cell Dev. Biol.

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Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.

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Ubiquitin-specific protease 7 downregulation suppresses breast cancer in vitro

Cited by 15 publications

References 47 publications

RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

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