Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells

Langlands, Alistair; Carroll, Thomas; Chen, Yu; Näthke, Inke

doi:10.1038/s41419-017-0199-9

Cited by 22 publications

(22 citation statements)

References 33 publications

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“…Furthermore, butyrate also enhances the barrier function of intestinal epithelial cells by up-regulating TJ protein claudin-1 (27). As HDAC inhibitors, butyrate, and valproic acid are important for maintaining stem cell populations, and stimulating normal cell growth in small intestinal organoid culture (13,28). SCFAs also induce different effects on immune cells in a cell-and environment-specific context.…”

Section: Disscussionmentioning

confidence: 99%

“…Both epithelial HDAC1 and HDAC2 contribute to regulation of the intestinal inflammatory response by regulating intestinal epithelial cell proliferation and differentiation (42). The HDAC inhibitor valproic acid is commonly used with GSK-3 inhibitor Chiron99021 in early passages for organoid culture to improve the efficiency of organoid formation because they can up-regulate Wnt and Notch signaling, resulting in the presence of more Lgr5+ stem cells (13,28). Interestingly, Langlands et al found that the combination of valproic acid and Chiron99021 restricts the growth advantage of Apc mutant (mutations in Adenomatous polyposis coli) organoid cells while stimulating the growth of wild-type cells, implying that HDAC inhibitors selectively protect the normal crypt stem cells in the intestine (28).…”

Section: Disscussionmentioning

confidence: 99%

“…The HDAC inhibitor valproic acid is commonly used with GSK-3 inhibitor Chiron99021 in early passages for organoid culture to improve the efficiency of organoid formation because they can up-regulate Wnt and Notch signaling, resulting in the presence of more Lgr5+ stem cells (13,28). Interestingly, Langlands et al found that the combination of valproic acid and Chiron99021 restricts the growth advantage of Apc mutant (mutations in Adenomatous polyposis coli) organoid cells while stimulating the growth of wild-type cells, implying that HDAC inhibitors selectively protect the normal crypt stem cells in the intestine (28). HDAC inhibition also attenuated morphine tolerance in a bone cancer pain model and facilitated extinction of morphine-induced conditioned place preference, suggesting that the interactions of HDAC and opioid receptors were crucial for host responses to opioid exposure (43).…”

Section: Disscussionmentioning

confidence: 99%

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Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice

et al. 2020

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Intestinal barrier dysfunction and subsequent microbial translocation play crucial roles in persistent immune activation leading to HIV disease progression. Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by excessive intestinal inflammation and increased gut permeability. The objective of this study is to investigate how opioids potentiate HIV disease progression by compromising intestinal barrier function and impairing intestinal epithelial self-repair mechanism. In the present study, abnormal intestinal morphology and reduced epithelial proliferation were observed in bone marrow-liver-thymus humanized mice and in HIV-infected patients who were exposed to opioids. In bone marrow-liver-thymus mice, HIV, and morphine independently, and additively induced gut dysbiosis, especially depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae. We also observed that the abundance of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae negatively correlated with apoptosis of epithelial cells, and intestinal IL-6 levels. Previous studies have shown that these bacterial families play crucial roles in maintaining intestinal homeostasis because they include most short-chain fatty acid-producing members. Short-chain fatty acids have been shown to maintain stem cell populations and suppress inflammation in the gut by inhibiting histone deacetylases (HDAC). In addition, we demonstrate that morphine exposure inhibited growth of intestinal organoids derived from HIV transgenic mice by suppressing Notch signaling in an HDAC-dependent manner. These studies implicate an important role for HDAC in intestinal homeostasis and supports HDAC modulation as a therapeutic intervention in improving care of HIV patients, especially in opioid-abusing population.

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Section: Disscussionmentioning

confidence: 99%

Section: Disscussionmentioning

confidence: 99%

Section: Disscussionmentioning

confidence: 99%

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Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice

et al. 2020

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“…The organoids initially displayed budding and were indistinguishable from healthy organoids, but spontaneously developed cystic morphology after several passages. This was congruent to the loss of heterozygosity of the APC gene 198,199 , correlating with the adenoma stage in vivo. I the adenoma stage in intestinal cancer.…”

Section: Repression Of Tcf7l2 Rescues Cystic Apc Min/small Intestine supporting

confidence: 58%

An inducible and reversible genetics platform for novel drug target discovery

Leong¹

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Undertaking my PhD at Nanyang Technological University has been both stimulating and enriching. I would like to thank the following people who have made this experience such an enjoyable one: Prof Klaus Karjalainen for his mentorship and invaluable expert advice. I am ever so grateful that he has given me the freedom to cultivate my ideas. Prof Christiane Ruedl for her kind concern and suggestions on how I can improve my work. Dr Piotr Tetlak who showed me the ropes around the lab and was actively involved in teaching and guiding me through the mouse transgenesis work.

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“…Since IL-22 has been implicated in promoting stemness and proliferation in colorectal cancer cell lines (Kryczek et al, 2014;Kirchberger et al, 2013;Lindemans et al, 2015), we asked how transformed SI epithelial cells responded to IL-22. We treated transformed Apc Min/Min SI organoids (Langlands et al, 2018) derived from Apc Min/+ mice with and performed RNASeq. In contrast to WT cells, we found only a minute number of genes regulated by IL-22…”

Section: Defective Il-22 Mediated Gene Regulation In Apc-mutant Iecmentioning

confidence: 99%

Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

Chen

Newton

Vandereyken

et al. 2018

Preprint

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Interleukin is critical in maintaining homeostasis in the intestine by regulating the balance between pathogenic and commensal bacteria. IL-22 also promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the tumour suppressor Adenomatous Polyposis Coli gene (Apc) cause intestinal tumorigenesis and are a major driver of familial colorectal cancers. To understand the role of IL-22 in APCmediated tumorigenesis, we analysed IL-22 signalling in wild-type (WT) and APC-mutant cells in murine small intestinal epithelial organoids and in mice. In WT epithelia, antimicrobial defence, mucus production, and cellular stress response pathways were most strongly upregulated by . Surprisingly, we found that although IL-22 activated STAT3 in APCmutant cells, STAT3 target genes were not effectively induced. Our analyses revealed that Apc Min/Min cells were resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, including histone deacetylases. We further show that IL-22 induced expression of nitric oxide synthase in WT epithelial cells and corresponding DNA damage. These findings suggest that IL-22 does not promotes tumour formation by driving the proliferation of transformed intestinal epithelial cells. Rather, IL-22 increases genetic instability thereby accelerating transition from heterozygosity (Apc Min/+ ) to homozygosity (Apc Min/Min ) to drive tumour progression. Chen Y. et al. 3

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Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells

Cited by 22 publications

References 33 publications

Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice

Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice

An inducible and reversible genetics platform for novel drug target discovery

Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

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