Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Liu, Yuan; Yu, Cuifu; Shao, Zhenlong; Xia, Xiaohong; Hu, Tumei; Kong, Weiyao; He, Xiaoyue; Sun, Wenshuang; Deng, Yuanfei; Liao, Yuning; Huang, Hongbiao

doi:10.1038/s41419-021-04162-0

Cited by 31 publications

(30 citation statements)

References 49 publications

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“…Flow cytometry analysis was performed as previously reported [ 55 ]. Apoptotic cells were assessed using FITC Annexin V Apoptosis Detection kit (Cat.…”

Section: Methodsmentioning

confidence: 99%

Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy

Wang

Qin

et al. 2022

Cell Death Dis

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Breast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.

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“…Flow cytometry analysis was performed as previously reported [ 55 ]. Apoptotic cells were assessed using FITC Annexin V Apoptosis Detection kit (Cat.…”

Section: Methodsmentioning

confidence: 99%

Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy

Wang

Qin

et al. 2022

Cell Death Dis

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“…Nobiletin is a plant flavonoid extracted from citrus peels and possesses broad anti-cancer activity ( 128 , 129 ). A recent study showed that Nobiletin moderately reduced AR-V7 protein level in 22RV-1 cells at 20 μM concentration and synergistically suppressed (at 40 mg/kg/2day) 22RV1 cell-derived xenograft tumor growth with Enzalutamide (20 mg/kg/2day) ( 53 ). The mechanistic study revealed that Nobiletin disrupted AR-V7 interaction with two deubiquitinases, USP14 and USP22, leading to proteasome-based AR-V7 degradation ( 53 ).…”

Section: Ar Protein Elimination Approaches In Preclinical Development...mentioning

confidence: 99%

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Huang

Lin

2022

Front. Oncol.

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Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

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“…Nobiletin is a natural product extracted from the peel and belongs to the polymethoxyflavonoids ( 72 ).Nobiletin mediates proteasomal degradation of AR-V7 by promoting ubiquitination of AR-V7 protein in CRPC cells ( 72 ). USP22 acts as a deubiquitinating enzyme that regulates the stability of AR-V7 protein.…”

Section: Resistance Mechanism Of Usp22mentioning

confidence: 99%

Immune Evasion and Drug Resistance Mediated by USP22 in Cancer: Novel Targets and Mechanisms

Guo

Zhao

et al. 2022

Front. Immunol.

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Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4+ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.

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Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Cited by 31 publications

References 49 publications

Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy

Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Immune Evasion and Drug Resistance Mediated by USP22 in Cancer: Novel Targets and Mechanisms

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