Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

Zhang, Zeda; Zhou, Chuanli; Li, Xiaoling; Barnes, Spencer; Deng, Su; Hoover, Elizabeth; Chen, Chi Chao; Lee, Young Sun; Zhang, Yanxiao; Wang, Choushi; Metang, Lauren A.; Wu, Chao; Tirado, Carla Rodriguez; Johnson, Nickolas A.; Wongvipat, John; Navrazhina, Kristina; Cao, Zhen; Choi, Danielle; Huang, Chen‐Hung; Linton, Eliot; Chen, Xiaoping; Liang, Yupu; Mason, Christopher E.; Stanchina, Elisa de; Abida, Wassim; Lujambio, Amaia; Li, Sheng; Lowe, Scott W.; Mendell, Joshua T.; Malladi, Venkat S.; Sawyers, Charles L.; Mu, Ping

doi:10.1016/j.ccell.2020.03.001

Cited by 117 publications

(182 citation statements)

References 82 publications

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“…Therefore, the increase in metastasis upon CHD1 loss was observed irrespective of the AR and PTEN status. Further studies are required to determine whether the prognostic role of CHD1 loss is independent of the AR signaling activity and PTEN status in patients since recent publications indicate a close relationship between CHD1 and AR, CHD1 and resistance to AR-targeted therapy as well as CHD1 and PTEN [21][22][23][24]. In a parallel study including 4986 patients with known CHD1 and PTEN status we determined the prognostic role of CHD1 loss in PTEN-wildtype vs -deleted patient subsets (Oh-Hohenhorst et al, in preparation).…”

Section: Discussionmentioning

confidence: 99%

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

et al. 2021

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The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33; p < 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.

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Section: Discussionmentioning

confidence: 99%

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

et al. 2021

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“…After CRISPR-deletion efficiency validation, we chose 4 pairs for functional experiments. Guide sequences were cloned into the Lentiviral CRISPR/Cas9 vectors that were previously described ( Mu et al, 2017 ; Zhang et al, 2020 ). All CRISPR-guide sequences and vector information were listed in the Key Resources Table .…”

Section: Methodsmentioning

confidence: 99%

Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

et al. 2020

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SUMMARY Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo . Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.

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“…To date, scientists have used ATAC-seq in cancer research and have obtained some encouraging results. Zhang et al applied ATAC-seq and RNAseq to reveal that CHD1 loss resulted in global changes in chromatin with associated transcriptomic change and it was also a factor underlying antiandrogen resistance in prostate cancer (12). Liu et al used ATAC-seq to reveal that CASZ1 regulates skeletal muscle genes by chromatin accessibility.…”

Section: Introductionmentioning

confidence: 99%

Bibliometric Analysis of ATAC-Seq and Its Use in Cancer Biology via Nucleic Acid Detection

et al. 2020

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Assay for transposase-accessible chromatin using sequencing (ATAC-seq) is associated with significant progress in biological research and has attracted increasing attention. However, the impact of ATAC-seq on cancer biology has not been objectively analyzed. We categorized 440 ATAC-seq publications according to the publication date, type, field, and country. R 3.6.2 was used to analyze the distribution of research fields. VOSviewer was used for country co-authorship and author co-authorship analyses, and GraphPad Prism 8 was used for correlation analyses of the factors that may affect the number of articles published in different countries. We found that ATAC-seq plays roles in carcinogenesis, anticancer immunity, targeted therapy, and metastasis risk predictions and is most frequently used in studies of leukemia among all types of cancer. We found a significantly strong correlation between the top 10 countries in terms of the number of publications and the gross expenditure on research and development (R&D), the number of universities, and the number of researchers. At present, ATAC-seq technology is undergoing a period of rapid development, making it inseparable from the emphasis and investment in scientific research by many countries. Collectively, ATAC-seq has advantages in the study of the cancer mechanisms because it can detect nucleic acids and thus has good application prospects in the field of cancer, especially in leukemia studies. As a country's economic strength increases and the emphasis on scientific research deepens, ATAC-seq will definitely play a more significant role in the field of cancer biology.

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Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

Cited by 117 publications

References 82 publications

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

Bibliometric Analysis of ATAC-Seq and Its Use in Cancer Biology via Nucleic Acid Detection

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