PRDM1 silences stem cell-related genes and inhibits proliferation of human colon tumor organoids

Liu, Changlong; Banister, Carolyn E.; Weige, Charles C.; Altomare, Diego; Richardson, Joseph H.; Buckhaults, Phillip

doi:10.1073/pnas.1802902115

Cited by 41 publications

(43 citation statements)

References 47 publications

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“…Several studies have identified an embryonic stem cell-like geneexpression signature in breast cancer (34) and in poorly differentiated aggressive human tumors (35), and such stem-like signatures usually correlate with poor prognosis. Our previous study proved that repressing stemness by epigenetic means can inhibit colorectal tumor organoid proliferation in a 3D culture system (21). We have also investigated p53 dependency of drug sensitivity in human colorectal cancer cell lines with and without TP53 deletions, and found that most of drugs have similar response patterns to what we report here in human embryonic stem cells ( Supplementary Fig.…”

Section: Discussionsupporting

confidence: 74%

“…TP53 knockout hESCs and RKO cells were generated using CRISPR/Cas9 as described previously (21) with minor modifications. Briefly, human codon-optimized Streptococcus pyogenes wild-type Cas9 (Cas9-2A-GFP) was obtained from Addgene (#44719).…”

Section: Tp53 Knockout In Human Embryonic Cells and Rko Cells With Crmentioning

confidence: 99%

“…To identify genes that could resensitize TP53 knockout cells to cisplatin, the sgRNAs counts from drug versus vehicle screens were analyzed using Model-based Analysis of Genome-wide CRISPR/ Cas9 Knockout (MAGeCK) method (21). The MAGeCK algorithm identifies both positively and negatively selected genes simultaneously and reports robust results across different experimental conditions.…”

Section: Gene Knockouts Causing Chromosome Missegregation Can Resensimentioning

confidence: 99%

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Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

2019

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TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDAapproved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53mutant cancers. Significance: These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.

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Section: Discussionsupporting

confidence: 74%

Section: Tp53 Knockout In Human Embryonic Cells and Rko Cells With Crmentioning

confidence: 99%

Section: Gene Knockouts Causing Chromosome Missegregation Can Resensimentioning

confidence: 99%

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Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

2019

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“…TP53 knockout MCF-7 cells were generated as previously published 45 . Human codonoptimized Streptococcus pyogenes wild type Cas9 (Cas9-2A-GFP) was obtained from Addgene (Cambridge, MA).…”

Section: Tp53 Knockout In Mcf-7 Cellsmentioning

confidence: 99%

Store Independent Ca²⁺Entry Regulates the DNA Damage Response in Breast Cancer Cells

Makena

Mekile

et al. 2020

Preprint

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Although the mainstay of treatment for hormone responsive breast tumors is targeted endocrine therapy, many patients develop de novo or acquired resistance and are treated with chemotherapeutic drugs. The vast majority (80%) of estrogen receptor positive tumors also express wild type p53 protein that is a major determinant of the DNA damage response. Tumors that are ER+ and p53 WT respond poorly to chemotherapy, although the underlying mechanisms are not completely understood. We describe a novel link between store independent Ca 2+ entry (SICE) and resistance to DNA damaging drugs, mediated by the secretory pathway Ca 2+ -ATPase, SPCA2. In luminal ER+/PR+ breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. Independent of ion pump activity, SPCA2 elevates baseline Ca 2+ levels through SICE and drives cell proliferation. Attenuation of SPCA2 or depletion of extracellular Ca 2+ increased mitochondrial ROS production, DNA damage and activation of the ATM/ATR-p53 axis leading to G0/G1 phase cell cycle arrest and apoptosis. Consistent with these findings, SPCA2 knockdown confers chemosensitivity to DNA damaging agents including doxorubicin, cisplatin and ionizing radiation. We conclude that elevated SPCA2 expression in ER+ p53 WT breast tumors drives pro-survival and chemotherapy resistance by suppressing the DNA damage response. Drugs that target storeindependent Ca 2+ entry pathways may have therapeutic potential in treating receptor positive breast cancer.

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“…As for other members of the PRDM family, the existence of an alternative protein product of the PRDM1 gene was previously described in myeloma cell lines; this protein, named PRDM1β, is generated by alternative transcription initiation using an internal promoter and it has a disrupted PR domain and lacks the amino-terminal 101 aa of the originally described protein [41]. Noteworthy, a recent study showed that PRDM1β was a p53-response gene in human colon organoids and low PRDM1 expression could predict poor survival in colon cancer patients [42]. However, today the functional role of these protein isoforms still needs to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Multifaceted Role of PRDM Proteins in Human Cancer

Casamassimi

Rienzo

Zazzo

et al. 2020

IJMS

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The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.

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PRDM1 silences stem cell-related genes and inhibits proliferation of human colon tumor organoids

Cited by 41 publications

References 47 publications

Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

Store Independent Ca²⁺Entry Regulates the DNA Damage Response in Breast Cancer Cells

Multifaceted Role of PRDM Proteins in Human Cancer

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PRDM1 silences stem cell-related genes and inhibits proliferation of human colon tumor organoids

Cited by 41 publications

References 47 publications

Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

Store Independent Ca2+Entry Regulates the DNA Damage Response in Breast Cancer Cells

Multifaceted Role of PRDM Proteins in Human Cancer

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Store Independent Ca²⁺Entry Regulates the DNA Damage Response in Breast Cancer Cells