G protein-coupled kisspeptin receptor induces metabolic reprograming and tumorigenesis in estrogen receptor-negative breast cancer

Dragan, Magdalena; Nguyen, Mai-Uyen; Guzman, Stephania; Goertzen, Cameron; Brackstone, Muriel; Dhillo, Waljit S.; Bech, Paul; Clarke, Sophie; Abbara, Ali; Tuck, Alan B.; Hess, David A.; Pine, Sharon R.; Zong, Wei Xing; Wondisford, Frederic E.; Su, Xiaoyang; Babwah, Andy V.; Bhattacharya, Moshmi

doi:10.1038/s41419-020-2305-7

Cited by 10 publications

(9 citation statements)

References 66 publications

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“…Immunohistochemical analysis revealed enriched KISS1R expression localized to the plasma membrane and cytosol in human NAFL and NASH liver samples, compared with that in healthy liver ( Figure 12C ). Next, plasma KP levels were examined in male patients with NAFL and/or NASH, compared with healthy participants, as previously described ( 69 , 70 ). Because the prevalence of NAFLD parallels the rise of T2D, plasma KP levels were also examined in patients with T2D.…”

Section: Resultsmentioning

confidence: 99%

“…However, KISS1R signaling in cancer appears to be context specific. Our earlier work has shown that, in triple-negative breast cancer (TNBC), KISS1R signaling promotes tumor growth and metastasis ( 70 ). When ERα is reexpressed in TNBC cells, KISS1R is downregulated, demonstrating that ERα negatively regulates KISS1R expression in TNBC ( 85 ).…”

Section: Discussionmentioning

confidence: 99%

“…When ERα is reexpressed in TNBC cells, KISS1R is downregulated, demonstrating that ERα negatively regulates KISS1R expression in TNBC ( 85 ). In native TNBC cells lacking ERα, KISS1R signaling promotes epithelial-mesenchymal transition, MAPK activation, and cancer growth and invasion ( 70 , 86 – 88 ). The role of KISS1 in HCC has not been clearly established, although loss of KISS1 in human HCC is associated with an upregulation of MMP9 and increased cell invasion ( 89 ), suggesting that KISS1 may function as a metastasis suppressor in HCC.…”

Section: Discussionmentioning

confidence: 99%

“…These results illustrate the translational relevance of our preclinical findings, as they mirror the results that we observed using HFD-fed mice. Changes in human plasma KP levels have been reported in puberty ( 93 ) and pregnancy ( 94 ) as well as in various cancers ( 69 , 70 , 95 ). In fact, in proof-of-concept studies, KP has been used to identify the cause of pubertal delay in children and to treat infertility in adults ( 96 – 98 ).…”

Section: Discussionmentioning

confidence: 99%

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Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

Guzman¹,

Dragan²,

Kwon³

et al. 2022

Journal of Clinical Investigation

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Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark featureof NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet–fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet–fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

Guzman¹,

Dragan²,

Kwon³

et al. 2022

Journal of Clinical Investigation

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“…Membranes were blocked for 2 h at room temperature in Blotto (5% milk in Tris-buffered saline). The membranes were incubated with an anti-AMH mouse monoclonal antibody (sc-365643) [22] (1:100 dilution; Santa Cruz Biotechnology, Inc., Dallas, TX), anti-AMHR2 rabbit polyclonal antibody (ab 197148) (1:1,000 dilution; Abcam, Cambridge, UK), anti-kisspeptin rabbit polyclonal antibody (ab 19028) [23] (1:100 dilution; Abcam), or anti-Kiss-1R rabbit polyclonal antibody (ab 137483) [24] (1:500 dilution; Abcam) in Blotto overnight at 4°C and washed for 10 min three times with Tris-buffered saline/1% Tween. A subsequent incubation with horseradish peroxidase (HRP)-conjugated secondary antibodies (anti-mouse antibody, 1:15,000 dilution; anti-rabbit antibody, 1:20,000 dilution) was performed for 1 h at room temperature in Blotto, and additional washes were performed as needed.…”

Section: Western Blot Analysismentioning

confidence: 99%

Effect of anti-Müllerian hormone on the regulation of pituitary gonadotropin subunit expression: roles of kisspeptin and its receptors in gonadotroph LβT2 cells

et al. 2021

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Anti-Müllerian hormone (AMH) is primarily produced by ovarian granulosa cells and contributes to follicle development. AMH is also produced in other tissues, including the brain and pituitary; however, its roles in these tissues are not well understood. In this study, we examined the effect of AMH on pituitary gonadotrophs. We detected AMH and AMH receptor type 2 expression in LβT2 cells. In these cells, the expression of FSHβ-but not α-and LHβ-subunits increased significantly as the concentration of AMH increased. LβT2 cells expressed Kiss-1 and Kiss-1R. AMH stimulation resulted in decreases in both Kiss-1 and Kiss-1R. The siRNA-mediated knockdown of Kiss-1 in LβT2 cells did not alter the basal expression levels of α-, LHβ-, and FSHβ-subunits. In LβT2 cells overexpressing Kiss-1R, exogenous kisspeptin stimulation significantly increased the expression of all three gonadotropin subunits. However, kisspeptin-induced increases in these subunits were almost completely eliminated in the presence of AMH. In contrast, GnRH-induced increases in the three gonadotropin subunits were not modulated by AMH. Our observations suggested that AMH acts on pituitary gonadotrophs and induces FSHβ-subunit expression with concomitant decreases in Kiss-1 and Kiss-1R gene expression. Kisspeptin, but not GnRH-induced gonadotropin subunit expression, was inhibited by AMH, suggesting that it functions in association with the kisspeptin/Kiss-1R system in gonadotrophs.

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Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells

Wang

Shannar

et al. 2022

Molecular Nutrition Food Res

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Scope: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. Methods and results: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. Conclusion: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.

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G protein-coupled kisspeptin receptor induces metabolic reprograming and tumorigenesis in estrogen receptor-negative breast cancer

Cited by 10 publications

References 66 publications

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

Effect of anti-Müllerian hormone on the regulation of pituitary gonadotropin subunit expression: roles of kisspeptin and its receptors in gonadotroph LβT2 cells

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells

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