DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals

Chen, Xiaoyu; Xiong, Xiufang; Cui, Di; Yang, Fei; Wei, Dongping; Li, Haomin; Shu, Jianfeng; Bi, Yanli; Dai, Xiao-Qing; Gong, Linghui; Sun, Yi; Zhao, Yongchao

doi:10.1038/s41388-019-1085-y

Cited by 30 publications

(25 citation statements)

References 55 publications

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“…Our results indicated that FDFT1 expression is negatively correlated with mTOR expression. Consistent with the data in previous reports 27,[57][58][59][60] , our data showed that mTOR is a positive regulator of aerobic glycolysis and proliferation in CRC cells. HIF1α is a key regulator of the Warburg effect and regulates the expression of a variety of metabolism-related proteins 61 .…”

Section: Discussionsupporting

confidence: 93%

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

et al. 2020

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Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/ HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

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Section: Discussionsupporting

confidence: 93%

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

et al. 2020

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“…Among genes that were co‐bound by HNF1A/KDM6A and downregulated in Kdm6a pKO and Hnf1a aKO pancreas, we identified several negative regulators of EMT such as Foxa3 (Jagle et al , ) and Deptor (Chen et al , ) as well as negative MAPK regulators such as Gstp1 (Ruscoe et al , ; Xue et al , ) and Ptprj (Sacco et al , ) (Fig EV3T and U). These findings, therefore, indicated that the derangement of shared biological pathways in Kdm6a pKO and Hnf1a aKO mice (shown in Fig EV3L) was largely due to the deregulation of common direct target genes.…”

Section: Resultsmentioning

confidence: 96%

HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer

et al. 2020

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Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysinespecific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with Kras G12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of nonclassical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumorsuppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

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“…This result is consistent with previous ndings. [31,32]. In addition, SOX2 as a stem-like transcription factor could promote EMT [32,33].…”

Section: Discussionmentioning

confidence: 99%

Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway

Qin

Sheng

Huang

et al. 2020

Preprint

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Background: Although Androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer, recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G(CIgG) was found to be induced after ADT, identifying CIgG as a potential CRPC driver gene.Methods: The expression of CIgG and its clinical significance in prostate cancer tissue was analyzed by TCGA database and immunohistochemistry. Subsequently, the sequence features of prostate cell line (LNcap, DU145, PC3) VHDJH rearrangements were analyzed via comparison with the best matching functional germline IgVH, IgDH and IgJH genes. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of prostate cancer cells in vitro and vivo. Cells with high CIgG expression (CIgGhigh) and low CIgG expression (CIgG-/low) from the PC3 cell line were sorted by FACS using a CIgG monoclonal antibody named RP215, then, suspended microsphere, colony formation and drug-resistant assays were performed. A NOD/SCID mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The AR-SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, qRT-PCR, Western blot, luciferase and ChIP assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of prostate cancer in vivo using a Babl/c nude mouse xenograft model.Results: We demonstrated that CIgG was induced by androgen deprivation therapy (ADT) and upregulated by SOX2 [SRY (sex determining region Y)-box 2] in prostate cancer, which may promote the development of CRPC. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through MARK/ERK and AKT in prostate cancer.Conclusion: Our data suggests that CIgG could be a driver of CRPC development, and that targeting the SOX2-CIgG axis may therefore inhibit CRPC development after ADT.

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DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals

Cited by 30 publications

References 55 publications

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer

Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway

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