USP11/LSH/CYP24A1 axis activation underlies calcium homeostasis and potentiates the resistance of colorectal cancer cells to ferroptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211866 | GEO | 2023/07/12
REPOSITORIES: GEO
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Project description:USP11/LSH/CYP24A1 axis activation underlies calcium homeostasis and potentiates the resistance of colorectal cancer cells to ferroptosis
| PRJNA872473 | ENA
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:Despite the emerging evidence of ferroptosis implicated in diverse pathological scenarios, molecular adaptors linking its oxidative inducers and chromatin as carrier of stable epigenetic memory for its propagation remain elusive. Here, we report the identification of two WD40 proteins DCAF8 and WDR76 as substrate adaptor and molecular inhibitor respectively of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of the chromatin remodeler LSH. Degradation analysis and CRL4-DCAF8 complex reconstitution demonstrate that CRL4DCAF8 is a bona fide E3 ligase for LSH. In contrast, WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4DCAF8-LSH complex assembly. Importantly, this opposing regulatory strategy is utilized in lipid hydroperoxide induced ferroptosis, and we identify key redox homeostasis genes significantly regulated by the DCAF8/WDR76/LSH axis through transcriptomic epistasis analysis. Such responsiveness could be attributed to increased ratio of DCAF8 over WDR76 for antagonistic LSH association accompanying ROS overproduction invoked decrease of TET-catalyzed DNA oxidation. Evaluation of epigenetic dynamics at DCAF8/WDR76/LSH-regulated gene promoters reveals linker histone H1- and LSH-associated transcriptional repression is coordinately removed in ferroptosis. Together with phenotypes driven by WDR76 and DCAF8 manipulations, these data identify DCAF8- and WDR76-governed LSH degradation as a crucial node in ferroptosis, tumorigenesis and senescence.
2021-06-09 | GSE135361 | GEO
Project description:Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment.
| S-EPMC10326026 | biostudies-literature
Project description:DNA methylation is critical for normal development and plays important roles in genome organization and transcriptional regulation. Although DNA methyltransferases have been identified, the factors that establish and contribute to genome-wide methylation patterns remain elusive. Here, we report a high-resolution cytosine methylation map of the murine genome modulated by Lsh, a chromatin remodeling family member that has previously been shown to regulate CpG methylation at repetitive sequences. We provide evidence that Lsh also controls genome-wide cytosine methylation at nonrepeat sequences and relate those changes to alterations in H4K4me3 modification and gene expression. Deletion of Lsh alters the allocation of cytosine methylation in chromosomal regions of 50 kb to 2 Mb and, in addition, leads to changes in the methylation profile at the 5â² end of genes. Furthermore, we demonstrate that loss of Lsh promotesâas well as preventsâcytosine methylation. Our data indicate that Lsh is an epigenetic modulator that is critical for normal distribution of cytosine methylation throughout the murine genome.
2011-05-19 | GSE29393 | 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:DNA methylation is critical for normal development and plays important roles in genome organization and transcriptional regulation. Although DNA methyltransferases have been identified, the factors that establish and contribute to genome-wide methylation patterns remain elusive. Here, we report a high-resolution cytosine methylation map of the murine genome modulated by Lsh, a chromatin remodeling family member that has previously been shown to regulate CpG methylation at repetitive sequences. We provide evidence that Lsh also controls genome-wide cytosine methylation at nonrepeat sequences and relate those changes to alterations in H4K4me3 modification and gene expression. Deletion of Lsh alters the allocation of cytosine methylation in chromosomal regions of 50 kb to 2 Mb and, in addition, leads to changes in the methylation profile at the 5M-CM-"M-BM-^@M-BM-2 end of genes. Furthermore, we demonstrate that loss of Lsh promotesM-CM-"M-BM-^@M-BM-^Tas well as preventsM-CM-"M-BM-^@M-BM-^Tcytosine methylation. Our data indicate that Lsh is an epigenetic modulator that is critical for normal distribution of cytosine methylation throughout the murine genome. Chromatin immunoprecipitation followed by genomic sequencing was used to compare H3K4me3 modifications between wild type murine embryonal fibroblast cell lines (MEFs) and Lsh-/-MEFs.
2011-05-19 | E-GEOD-29393 | biostudies-arrayexpress
Project description:Purpose: We aimed to determine whether the expression of either wild-type or catalytically inactive LSH, carrying a single point mutation in its ATP binding site (K237Q), could restore the levels and patterns of DNA methylation in Lsh-/- mouse embryonic fibroblasts (MEFs). Methods: Lsh-/- MEFs were transduced with lentiviral particles carrying empty pMSCV vector, pMSCV-LSH-3xFLAG and pMSCV-LSH K/Q-3xFLAG, respectively. Clonal cell lines were generated and tested for LSH expression. Two independent cell lines expressing wild-type LSH and two expressing LSH K/Q were used for further analyses and comparison with wild-type MEFs and Lsh-/- MEFs carrying the empty vector. Genomic DNA was purified from all six cell lines and methylated DNA immunoprecipitation (MeDIP) was performed as described in Weber et al., 2007, Nat Genetics. MeDIP libraries were generated and sequenced on Illumina HiSeq 2000 instrument. Results and conclusions: Our experiments demonstrate that the expression of wild-type LSH, but not the catalytically inactive LSH K/Q, in Lsh-/- MEFs leads to reestablishment of DNA methylation at repetitive sequences and unique developmentally regulated loci in a cell-autonomous manner.
2016-07-21 | GSE64384 | GEO
Project description:We report here differences in MNase digestibility comparing murine embryonic fibroblasts (MEFs) with and without Lsh. In the first set of samples we compare primary MEFs derived from Lsh+/+ (pMEF_WT5) or Lsh-/- (pMEF_KO6) day 13.5 gestation embryos. In a second set we compare MEFs form conditional Lsh knockout mice before (GC-OHT-NC) or after 48 hours of tamoxifen inducible cre-recombinase expression (GC-OHT-2D). In a third set we compare Lsh knockout (Lsh cko) MEFs before (IAA-0h) and after 72 hours of IAA induced proteolytical degradation of Lsh (IAA-3D). In a fourth set we compare Lsh knockout MEFs before (IAA-0h-2) and after 7 hours of IAA induced proteolytical degradation of Lsh (IAA-7h) or after 24 hours (IAA-24). Lsh depletion leads to specific changes in chromatin accessibility at potential enhancer sites.
2019-03-28 | GSE103043 | GEO