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前列腺癌细胞中的3D CRISPR筛选揭示了通过TBL1XR1-SMC3相互作用使PARP抑制剂致敏的机制。

3D CRISPR screen in prostate cancer cells reveals PARP inhibitor sensitization through TBL1XR1-SMC3 interaction.

作者信息

Zhang Huan, Gao Huanyao, Gu Yayun, John August, Wei Lixuan, Huang Minhong, Yu Jia, Adeosun Adeyemi A, Weinshilboum Richard M, Wang Liewei

机构信息

School of Medicine, Nantong University, Nantong, China.

Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States.

出版信息

Front Oncol. 2022 Nov 29;12:999302. doi: 10.3389/fonc.2022.999302. eCollection 2022.

DOI:10.3389/fonc.2022.999302
PMID:36523978
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9746894/
Abstract

Poly(ADP-ribose) (PAR) polymerase inhibitors (PARPi) either have been approved or being tested in the clinic for the treatment of a variety of cancers with homologous recombination deficiency (HRD). However, cancer cells can develop resistance to PARPi drugs through various mechanisms, and new biomarkers and combination therapeutic strategies need to be developed to support personalized treatment. In this study, a genome-wide CRISPR screen was performed in a prostate cancer cell line with 3D culture condition which identified novel signals involved in DNA repair pathways. One of these genes, TBL1XR1, regulates sensitivity to PARPi in prostate cancer cells. Mechanistically, we show that TBL1XR1 interacts with and stabilizes SMC3 on chromatin and promotes γH2AX spreading along the chromatin of the cells under DNA replication stress. TBL1XR1-SMC3 double knockdown (knockout) cells have comparable sensitivity to PARPi compared to SMC3 knockdown or TBL1XR1 knockout cells, and more sensitivity than WT cells. Our findings provide new insights into mechanisms underlying response to PARPi or platin compounds in the treatment of malignancies.

摘要

聚（ADP-核糖）（PAR）聚合酶抑制剂（PARPi）已被批准或正在临床试验中用于治疗多种具有同源重组缺陷（HRD）的癌症。然而，癌细胞可通过多种机制对PARPi药物产生耐药性，因此需要开发新的生物标志物和联合治疗策略以支持个性化治疗。在本研究中，我们在具有三维培养条件的前列腺癌细胞系中进行了全基因组CRISPR筛选，确定了DNA修复途径中涉及的新信号。其中一个基因TBL1XR1可调节前列腺癌细胞对PARPi的敏感性。从机制上讲，我们发现TBL1XR1与染色质上的SMC3相互作用并使其稳定，并在DNA复制应激下促进γH2AX沿细胞染色质扩散。与SMC3敲低或TBL1XR1敲除细胞相比，TBL1XR1-SMC3双敲低（敲除）细胞对PARPi具有相当的敏感性，且比野生型细胞更敏感。我们的研究结果为恶性肿瘤治疗中对PARPi或铂类化合物反应的潜在机制提供了新见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/05c26b6b1f11/fonc-12-999302-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/e861fa41a3f0/fonc-12-999302-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/6e055bb3ca1f/fonc-12-999302-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/113463bc2308/fonc-12-999302-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/6dae7396770f/fonc-12-999302-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/d1cf8958c6de/fonc-12-999302-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/05c26b6b1f11/fonc-12-999302-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/e861fa41a3f0/fonc-12-999302-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/6e055bb3ca1f/fonc-12-999302-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/113463bc2308/fonc-12-999302-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/6dae7396770f/fonc-12-999302-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/d1cf8958c6de/fonc-12-999302-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff6d/9746894/05c26b6b1f11/fonc-12-999302-g006.jpg

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