CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis

Jang, Min Jun; Park, Ui-Hyun; Kim, Jeong Woo; Choi, Hanbyeul; Um, Soo‐Jong; Kim, Eun-Joo

doi:10.1038/s41419-017-0070-z

Cited by 31 publications

(22 citation statements)

References 34 publications

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“…Even though it is best studied in the hematopoietic and neuronal systems, LSD1 has emerged as a broader regulator of tissue stemness and differentiation, as recent reports indicate. In brief, LSD1 was implicated in spermatogenesis [62,63] and adipogenesis [64,65], while its loss promoted differentiation of mesenchymal stem cells towards bone or liver [66][67][68][69][70][71]. In a different context, LSD1 was required by the satellite cells (stem cells of muscle) for myogenic regeneration after injury [72] or for proper myoblast differentiation [73].…”

Section: Lsd1 In Other Normal Stem Cell Typesmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

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Section: Lsd1 In Other Normal Stem Cell Typesmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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“…To investigate how the histone codes are differentially enriched, we performed additional ChIP assays using antibodies against the histone‐modifying enzymes, histone acetyltransferase CBP, H3K4 methyltransferase Mll2, H3K9 demethylase Lsd1, H3K27 demethylase Utx, and H3K27 methyltransferase Ezh2. These enzymes are known to modulate adipogenesis alone or in cooperation with PPARγ (Dreijerink et al, ; Jang et al, ; Mizukami & Taniguchi, ; Ota et al, ; Wang, Jin, Lee, Su, & Ge, ). Upon piperine treatment, PPARγ coactivators, including CBP, Mll2, and Lsd1, dissociate from the PPARγ‐responsive element of the Fabp4 gene (Figure a).…”

Section: Resultsmentioning

confidence: 99%

Piperine inhibits adipocyte differentiation via dynamic regulation of histone modifications

Park

Youn

Kim

et al. 2019

Phytotherapy Research

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Previously, we reported that piperine, one of the major pungent components in black pepper, attenuates adipogenesis by repressing PPARγ activity in 3T3‐L1 preadipocytes. However, the epigenetic mechanisms underlying this activity remain unexplored. Here, gene set enrichment analysis using microarray data indicated that there was significant downregulation of adipogenesis‐associated and PPARγ target genes and upregulation of genes bound with H3K27me3 in response to piperine. As shown by Gene Ontology analysis, the upregulated genes are related to lipid oxidation and polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation assays revealed that PPARγ (and its coactivators), H3K4me3, and H3K9ac were less enriched at the PPAR response element of three adipogenic genes, whereas increased accumulation of H3K9me2, H3K27me3, and Ezh2 was found, which likely led to the reduced gene expression. Further analysis using three lipolytic genes revealed the opposite enrichment pattern of H3K4me3 and H3K27me3 at the Ezh2 binding site. Treatment with GSK343, an Ezh2 inhibitor, elevated lipolytic gene expression by decreasing the enrichment of H3K27me3 during adipogenesis, which confirms that Ezh2 plays a repressive role in lipolysis. Overall, these results suggest that piperine regulates the expression of adipogenic and lipolytic genes by dynamic regulation of histone modifications, leading to the repression of adipocyte differentiation.

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“…For example, H3K9ac levels are decreased during adipogenic differentiation of human amniotic fluid mesenchymal stem cells [38], whereas the acetyl histone level is unchanged in the adipocyte overdevelopment of bone-marrow stromal cells from glucocorticoid-mediated osteoporotic rats [39]. Jang et al report that the acetyl histone is increased in the adipocyte formation of murine 3T3-L1 adipogenic progenitor cells [40]. This study uncovered that H3K9ac-binding PPARγ2 promoter was unaffected, whereas PPARγ2 transcription and adipocytic activity were upregulated in glucocorticoid-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1

Wang

Chen

et al. 2020

Cells

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Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl–histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis.

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CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis

Cited by 31 publications

References 34 publications

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Piperine inhibits adipocyte differentiation via dynamic regulation of histone modifications

Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1

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