KDM4A promotes NEPC progression through regulation of MYC expression [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227688 | GEO | 2026/01/28
REPOSITORIES: GEO
Dataset's files
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| GSE227688_RAW.tar | Raw | |||
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Project description:Following extensive treatment with androgen receptor (AR) pathway inhibitors, a significant number of metastatic prostate cancer develop treatment resistance, and approximately 20% of these castration-resistant prostate cancers (CRPC) transdifferentiate, at least partially, into neuroendocrine (NE) prostate cancer (NEPC).In human cancer, FOXA2 is highly expressed in most of NEPC and a small portion of CRPC patients, has been suggested as a marker of NEPC and elevated in other NE lineage cancers including SCLC. In addition, preclinical studies demonstrated that Foxa2 is required for NEPC tumor growth and metastasis in TRAMP mouse model and associated with NEPC transformation in Pten, Trp53, and Rb1 triple knockout mouse model. However, whether FOXA2 is an essential driver of NEPC, and the underlying mechanism in shaping epigenetic landscape of NEPC is largely unknown.
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Project description:Following extensive treatment with androgen receptor (AR) pathway inhibitors, a significant number of metastatic prostate cancer develop treatment resistance, and approximately 20% of these castration-resistant prostate cancers (CRPC) transdifferentiate, at least partially, into neuroendocrine (NE) prostate cancer (NEPC).In human cancer, FOXA2 is highly expressed in most of NEPC and a small portion of CRPC patients, has been suggested as a marker of NEPC and elevated in other NE lineage cancers including SCLC. In addition, preclinical studies demonstrated that Foxa2 is required for NEPC tumor growth and metastasis in TRAMP mouse model and associated with NEPC transformation in Pten, Trp53, and Rb1 triple knockout mouse model. However, whether FOXA2 is an essential driver of NEPC, and the underlying mechanism in shaping epigenetic landscape of NEPC is largely unknown.
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Project description:To investigate the role of KDM4A in the regulation of gene expression in NEPC cells, we established Kdm4a KD cell lines in which Kdm4a gene has been knocked down by shRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at two time points.
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Project description:Histone lysine demethylase KDM4A is overexpressed in prostate cancer and plays a crucial role in tumor growth and survival. To understand the mechanisms underlying KDM4A-depedent cell growth and survival, microarray analysis was performed in LNCaP cells transduced with control or KDM4A specific-knockdown construct. The role of KDM4A in prostate carcinogenesis involves activation of E2F1 and androgen receptor transcriptional profiles. LNCaP cells were transduced by lentivirus carrying control pLKO.1 (empty vector) or shKDM4A construct (KDM4A-specific shRNA) for three days, followed by RNA extraction. Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays were used for microarray analysis.
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Project description:Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cancer cell survival, including in prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, a subset of tumors undergoes cellular reprogramming to a more lethal neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, role of LSD1 in NEPC is largely unknown. We sought to identify key genes and molecular pathways controlled by LSD1 in NEPC. We therefore inhibited LSD1 with SP2509 and performed RNA-seq in LASCPC-01, LNCaP-N-Myc, and MR42D cell lines. The vast majority of differentially expressed genes after SP2509 treatment were upregulated, suggesting that LSD1 may primarily function as a transcriptional repressor in NEPC. RNA-seq analysis reveals that LSD1 represses pathways linked to luminal differentiation and TP53 is the top pathway reactivated after LSD1 suppression. Taken together, these data suggest that LSD1 may be an important regulator of TP53 function in prostate cancer.
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Project description:Histone lysine demethylase KDM4A is overexpressed in prostate cancer and plays a crucial role in tumor growth and survival. To understand the mechanisms underlying KDM4A-depedent cell growth and survival, microarray analysis was performed in LNCaP cells transduced with control or KDM4A specific-knockdown construct. The role of KDM4A in prostate carcinogenesis involves activation of E2F1 and androgen receptor transcriptional profiles.
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Project description:Metastasis to the brain is rare in prostate cancer and unfortunately, incredibly lethal. We evaluated the tissue biopsies of a patient with a treatment-induced metastatic lesion to the brain of the neuroendocrine prostate cancer (NEPC) subtype. We performed genomic, transcriptomic, and proteomic characterization on the primary prostate tumor, the metastatic brain NEPC, and an additional metastatic nodule in the dura with adenocarcinoma histology. These data are the proteomics result of this patient, with three replicates for each sample (primary prostate, dura adenocarcinoma, brain NEPC).
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Project description:Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMT) are highly expressed, and global DNA methylation levels are elevated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and markedly reduced NEPC tumor development and metastasis in vivo. Decitabine, a global DNMT inhibitor, significantly attenuated tumor growth in NEPC patient-derived xenograft (PDX) models, as well as RB1-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1-proficient CRPC. We further discovered that DNMT inhibition increased expression of B7-H3, an emerging druggable target, via demethylation of B7-H3 CpG islands. We tested DS-7300a, a novel antibody-drug conjugate (ADC) targeting B7-H3, alone and in combination with decitabine. There was potent single agent antitumor activity of DS-7300a in both CRPC and NEPC models bearing high expression of B7-H3. In B7-H3 low models, combination therapy of decitabine plus DS-7300a resulted in a synergistic response. Overall, we report that DNMT inhibition is a novel therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to the ADC DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis. The development of novel biomarker-driven therapeutic strategies for this population may ultimately help improve patient outcomes.
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Project description:Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMT) are highly expressed, and global DNA methylation levels are elevated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and markedly reduced NEPC tumor development and metastasis in vivo. Decitabine, a global DNMT inhibitor, significantly attenuated tumor growth in NEPC patient-derived xenograft (PDX) models, as well as RB1-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1-proficient CRPC. We further discovered that DNMT inhibition increased expression of B7-H3, an emerging druggable target, via demethylation of B7-H3 CpG islands. We tested DS-7300a, a novel antibody-drug conjugate (ADC) targeting B7-H3, alone and in combination with decitabine. There was potent single agent antitumor activity of DS-7300a in both CRPC and NEPC models bearing high expression of B7-H3. In B7-H3 low models, combination therapy of decitabine plus DS-7300a resulted in a synergistic response. Overall, we report that DNMT inhibition is a novel therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to the ADC DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis. The development of novel biomarker-driven therapeutic strategies for this population may ultimately help improve patient outcomes.
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