USP11 promotes prostate cancer progression by upregulating AR and c-Myc activity [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1114716 | ENA |
REPOSITORIES: ENA
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Project description:Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer. USP11 expression was upregulated in metastatic prostate cancer and CRPC. USP11 knockdown significantly inhibited prostate cancer cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 knockdown. ChIP-seq analysis showed that either USP11 knockdown or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to upregulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability; deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc re-expression in USP11-knockdown prostate cancer cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive prostate cancer through upregulation of AR and c-Myc activities and support USP11 as a potential target against prostate cancer.
2024-07-13 | GSE268124 | GEO
Project description:Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer. USP11 expression was upregulated in metastatic prostate cancer and CRPC. USP11 knockdown significantly inhibited prostate cancer cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 knockdown. ChIP-seq analysis showed that either USP11 knockdown or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to upregulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability; deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc re-expression in USP11-knockdown prostate cancer cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive prostate cancer through upregulation of AR and c-Myc activities and support USP11 as a potential target against prostate cancer.
2024-07-13 | GSE268252 | GEO
Project description:USP11 promotes prostate cancer progression by upregulating AR and c-Myc activity [CUT&RUN]
| PRJNA1115793 | ENA
Project description:Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. A significant subset of patients with resistant disease develop AR-null, androgen-indifferent tumors that lose their luminal identify and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). Utilizing a genetically engineered mouse model, we have characterized the synergy between N-Myc overexpression and RB1 loss-of-function which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking changes to the transcriptome and chromatin accessibility during the transition to NEPC. Global DNA methylation and the N-Myc cistrome are redirected following RB1 loss. Altogether, our data provide new insight into the progression to NEPC.
2021-04-07 | GSE151581 | GEO
Project description:We examined gene expression level in KYSE410 cells expressing control, USP11 or ARID1A-targeting shRNAs to study the mechanism underlying the tumor suppressive effect of ARID1A and USP11.
2019-11-30 | GSE132359 | GEO
Project description:Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. A significant subset of patients with resistant disease develop AR-null, androgen-indifferent tumors that lose their luminal identify and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). Utilizing a genetically engineered mouse model, we have characterized the synergy between N-Myc overexpression and RB1 loss-of-function which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking changes to the transcriptome and chromatin accessibility during the transition to NEPC. Global DNA methylation and the N-Myc cistrome are redirected following RB1 loss. Altogether, our data provide new insight into the progression to NEPC.
2021-04-07 | GSE158468 | GEO
Project description:Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. A significant subset of patients with resistant disease develop AR-null, androgen-indifferent tumors that lose their luminal identify and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). Utilizing a genetically engineered mouse model, we have characterized the synergy between N-Myc overexpression and RB1 loss-of-function which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking changes to the transcriptome and chromatin accessibility during the transition to NEPC. Global DNA methylation and the N-Myc cistrome are redirected following RB1 loss. Altogether, our data provide new insight into the progression to NEPC.
2021-04-07 | GSE158467 | GEO
Project description:Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. A significant subset of patients with resistant disease develop AR-null, androgen-indifferent tumors that lose their luminal identify and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). Utilizing a genetically engineered mouse model, we have characterized the synergy between N-Myc overexpression and RB1 loss-of-function which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking changes to the transcriptome and chromatin accessibility during the transition to NEPC. Global DNA methylation and the N-Myc cistrome are redirected following RB1 loss. Altogether, our data provide new insight into the progression to NEPC.
2021-04-07 | GSE151425 | GEO
Project description:Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. A significant subset of patients with resistant disease develop AR-null, androgen-indifferent tumors that lose their luminal identify and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). Utilizing a genetically engineered mouse model, we have characterized the synergy between N-Myc overexpression and RB1 loss-of-function which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking changes to the transcriptome and chromatin accessibility during the transition to NEPC. Global DNA methylation and the N-Myc cistrome are redirected following RB1 loss. Altogether, our data provide new insight into the progression to NEPC.
2021-04-07 | GSE151424 | GEO
Project description:Hes6 is a transcription co-factor that is associated with stem cell characteristics in neural tissue, but its role in cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and the AR and can drive castration resistance in xenografts of the androgen-dependent LNCaP prostate cancer cell line model. Hes6 activates a cell cycle enhancing transcriptional network that maintains tumour growth in the absence of circulating androgen but with maintained nuclear AR. We demonstrate interaction between E2F1, the AR and Hes6 and show the co-dependency of these factors in the castration-resistant setting. In the clinical setting, we have discovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which could be pharmacologically targeted. Myc ChIPseq on LNCaP cells.
2014-04-17 | E-GEOD-37617 | biostudies-arrayexpress