A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance

Liao, Yuning; Liu, Yuan; Shao, Zhenlong; Xia, Xiaohong; Deng, Yuanfei; Cai, Jianyu; Yao, Leyi; He, Jinchan; Yu, Cuifu; Hu, Tumei; Sun, Wenshuang; Liu, Fang; Tang, Daolin; Liu, Jinbao; Huang, Hongbiao

doi:10.1038/s41388-021-01851-0

Cited by 20 publications

(29 citation statements)

References 38 publications

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“…Various studies have been demonstrated that reactivation of AR that resulted from the genetic mutation and amplification, increased stability, and expressions of splice variants, may be the major mechanism that contributes to the progress from the androgen-dependent PC to CRPC 4 , 26 , 33 - 35 . Our previous study demonstrated a novel mechanism that SIX1 signal can also contribute to the progression of CRPC 20 . Our current study demonstrated that the SIX1 degradation inducer can elevate the responsiveness of CRPC cells to the anti-AR therapy, consistently supporting that SIX1 is a druggable target for overcoming CRPC.…”

Section: Discussionmentioning

confidence: 97%

“…CDK1 siRNA-1: 5'-GGTTATATCTCATCTTTGA-3'; CDK1 siRNA-2: 5'-GTACTGCAATTCGGGAA AT-3'; CDK2 siRNA-1: 5'-GCACCAAGATCTCAAGAAA-3'; CDK2 siRNA-2: 5'- GGATGTGACCAAGCCAGTA-3'; CDK7 siRNA-1: 5'-CAACCAAATTGTCGCCA TT-3'; CDK7 siRNA-2: 5'-CTTACTAGATCTCATACAA-3'; CDK9 siRNA-1: 5'-GC CAAACGTGGACAACTAT-3'; CDK9 siRNA-2: 5'-ACGAGAAGCTCGCCAAGAT -3'. Plasmid transfection was performed as previously reported 20 .…”

Section: Methodsmentioning

confidence: 99%

“…As previously reported 20 , cells were seeded on a chamber slide (Thermo Fisher) and treated as indicated figure legends. At the end of cell culture, cells were washed with PBS for three times and fixed with 4% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

“…As previously reported, total RNAs isolated from PC cells were subjected to the RT-PCR experiment 20 . Table S1 lists the PCR primers for GLUT1, LDHA, HK2, USP1, and SIX1.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous report demonstrated that the expression and stabilization of SIX1 is highly controlled by mitochondria chaperone glucose-regulated protein 75 (GRP75) and ubiquitin specific peptidase 1 (USP1). GRP75 and USP1 can bind to SIX1 and form the “GRP75-USP1-SIX1” complex to prevent degradation of SIX1 from the proteasome, which further boosts the growth and castration resistance of PC 20 .…”

Section: Introductionmentioning

confidence: 99%

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A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

et al. 2022

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Prostate cancer (PC) remains a great medical challenge due to its high incidence and the development of castration resistance in patients treated with androgen deprivation therapy. Deubiquitinases, the enzymes that specifically hydrolyze ubiquitin chains on their substrates, were recently proposed as a serious of critical therapeutic targets for cancer treatment. Our previous study has been reported that the ubiquitin specific peptidase 1 (USP1) functionally acts as a deubiquitinase of sine oculis homeobox homolog 1 (SIX1) and contributes to the proliferation and castration resistance of PC. The stabilization of SIX1 by USP1 partially depends on the status of glucose-regulated protein 75 (GRP75). In this study, we aimed to identify a SIX1 degradation inducer via inhibiting the USP1-SIX1 axis. we screened a range of kinase inhibitors and showed that SNS-032 is the best candidate to trigger the ubiquitinated degradation of SIX1. SNS-032 not only restrains activity of the USP1-SIX1 axis and cell cycle progression, but also results in apoptosis of PC cells. Moreover, the combination of SNS-032 and enzalutamide synergistically induces apoptosis and downregulates expression of USP1, SIX1, and AR/AR-V7 in AR-V7 highly expressed 22Rv1 cells. Overall, our findings may develop a novel and effective strategy to overcome castration resistance in PC for the identification of a SIX1 degradation inducer via targeting the USP1-SIX1 axis.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…As previously reported, total RNAs isolated from PC cells were subjected to the RT-PCR experiment 20 . Table S1 lists the PCR primers for GLUT1, LDHA, HK2, USP1, and SIX1.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

et al. 2022

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HSP90β Impedes STUB1‐Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma

Liao

Liu

et al. 2023

Advanced Science

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YTH domain family 2 (YTHDF2) is the first identified N6‐methyladenosine (m6A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90β) and STIP1 homology and U‐box‐containing protein 1 (STUB1) physically interact with YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of HSP90β is required for its interaction with STUB1 and YTHDF2. HSP90β inhibits the STUB1‐induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90β and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90β is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90β. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC.

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Targeting deubiquitinases for cancer therapy

Xue,

Tang,

Chen

et al. 2023

Clinical and Translational Dis

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The ubiquitin‐proteasome system assumes a critical role in numerous cellular processes, and among its components, deubiquitinases (DUBs) have emerged as essential regulators. With roughly 100 DUBs encoded within the human genome, these enzymes can be categorized into two main types: cysteine protease DUBs and metalloproteinase DUBs, based on the catalytic mechanism of the active site. DUBs exert significant influence over specific substrates implicated in cancer progression, establishing them as closely associated with various malignancies, including breast carcinoma, prostate cancer, and chronic myeloid leukemia. Consequently, the targeted inhibition of DUBs presents an enticing therapeutic strategy for cancer treatment. Here, we delve into the functional roles of DUBs in different cancer types and provide a thorough overview of the anticancer properties exhibited by DUB inhibitors. This knowledge will propel the development and clinical application of DUB inhibitors, opening promising avenues for tumor treatment.

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A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance

Cited by 20 publications

References 38 publications

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

HSP90β Impedes STUB1‐Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma

Targeting deubiquitinases for cancer therapy

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