Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation

Liu, Jingping; Hanavan, Paul D.; Kras, Katon A.; Ruiz, Yvette; Castle, Erik P.; Lake, Douglas F.; Chen, Xianfeng; O’Brien, Daniel R.; Luo, Huijun; Robertson, Keith D.; Gu, Haiwei; Ho, Thai H.

doi:10.1021/acs.jproteome.8b00628

Cited by 32 publications

(37 citation statements)

References 31 publications

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“…Thus, FL clones show EMT, cell-proliferation, oxidative phosphorylation genes while EL clones maintain epithelial markers. Interestingly, ccRCC is also characterized by EMT, cell cycle activation and oxidative phosphorylation [29][30][31] indicating resemblance between ccRCC and FL clones. More specifically, the proximal markers SLC17A3 and VCAM1 that are both highly elevated in FL clones (Fig.…”

Section: Molecular Characterization Of Clone Types Reveal Sub-lineagementioning

confidence: 99%

Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

Cohen-Zontag

Gershon

Harari‐Steinberg

et al. 2020

Sci Rep

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In-vivo single cell clonal analysis in the adult mouse kidney has previously shown lineage-restricted clonal proliferation within varying nephron segments as a mechanism responsible for cell replacement and local regeneration. To analyze ex-vivo clonal growth, we now preformed limiting dilution to generate genuine clonal cultures from one single human renal epithelial cell, which can give rise to up to 3.4 * 106 cells, and analyzed their characteristics using transcriptomics. A comparison between clonal cultures revealed restriction to either proximal or distal kidney sub-lineages with distinct cellular and molecular characteristics; rapidly amplifying de-differentiated clones and a stably proliferating cuboidal epithelial-appearing clones, respectively. Furthermore, each showed distinct molecular features including cell-cycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers. In addition, analysis of clonal versus bulk cultures show early clones to be more quiescent, with elevated expression of renal developmental genes and overall reduction in renal identity markers, but with an overlapping expression of nephron segment identifiers and multiple identity. Thus, ex-vivo clonal growth mimics the in-vivo situation displaying lineage-restricted precursor characteristics of mature renal cells. These data suggest that for reconstruction of varying renal lineages with human adult kidney based organoid technology and kidney regeneration ex-vivo, use of multiple heterogeneous precursors is warranted.

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Section: Molecular Characterization Of Clone Types Reveal Sub-lineagementioning

confidence: 99%

Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

Cohen-Zontag

Gershon

Harari‐Steinberg

et al. 2020

Sci Rep

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“…The low expression of SETD2 leads to proliferative advantage, increased colony formation and accelerated leukemia development of fusion-protein expressing cancer cells in MLL [38]. Similar reports are common in cancers such as renal cell carcinoma and pancreatic cancer [39,40]. In addition to EZH2 and SETD2, KMTs such as G9a [41,42], MLL [43], DOT1L [44] and NSD1 [45] are associated with tumor development and progression.…”

Section: Kmts and Tumor Biological Characteristicsmentioning

confidence: 54%

Histone methyltransferase and drug resistance in cancers

Yang

Zhang

et al. 2020

J Exp Clin Cancer Res

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A number of novel anticancer drugs have been developed in recent years. However, the mortality of cancer patients remains high because of the emergence of drug resistance. It was reported that drug resistance might involved in changes in gene expression without changing genotypes, which is similar to epigenetic modification. Some studies indicated that targeting histone methyltransferase can reverse drug resistance. Hence, the use of histone methyltransferase inhibitors or histone demethylase inhibitors opens new therapeutic approaches for cancer treatment. While the relationship between histone methyltransferase and tumor resistance has been determined, there is a lack of updated review on the association between them. In this review, we summarized the mechanisms of histone methyltransferases in cancer drug resistance and the therapeutic strategies of targeting histone methyltransferase to reverse drug resistance.

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“…Interestingly, ccRCC markers such as ITGA5, GGT1, CDH6 and CA9 were also found to be upregulated in FL clones (Figure S4B). ccRCC is also characterized by EMT, cell cycle activation and oxidative phosphorylation [24-26] further supporting the resemblance between ccRCC and FL clones.…”

Section: Resultsmentioning

confidence: 93%

Molecular characterization of clonal human renal forming cells

Osnat

Rotem

Orit

et al. 2020

Preprint

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The adult kidney replaces its parenchyma in vivo in steady state and during regeneration by segment-specific clonal cell proliferation.To understand human adult kidney clonal cell growth, we derived tissue from human nephrectomies and performed limiting dilution to establish genuine clonal cultures from one single cell.Clonal efficiency of the human kidney was x%. Remarkably, a single renal cell could give rise to up to 3.3*10(6) cells. Phenotypically, two types of clonal cultures were apparent; a stably proliferating cuboidal epithelial-like appearing (EL) and a rapidly proliferating fibroblast-like appearing (FL). RNA sequencing of all clonal cultures separated FL from EL cultures according to proximal-distal/collecting renal epithelial tubular identity, respectively. Moreover, distinct molecular features in respect to cellcycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers were observed for each clone type. Surprisingly, clonal expansion (>3 months) was sustained in EL clones harboring markers of mature kidney epithelia (high CD24, CDH1, EpCAM, EMA) in contrast to dedifferentiated FL clones (high NCAM1, serpine1), which showed fast lineage amplification and exhausted in a few weeks. Thus, the human adult kidney harbors progenitor cell function in which segment identity and the level of epithelial differentiation dictate clonal characteristics.2 4 . Liu, J., et al., Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation . J Proteome Res, 2019. 18(1): p. 331-340.2 5 . , L., et al., Clear Cell Renal Cell Carcinoma is linked to Epithelial-to-Mesenchymal Transition and to Fibrosis. Physiol Rep, 2017. 5(11.( 2 6 . Sanchez, D.J. and M.C. Simon, Genetic and metabolic hallmarks of clear cell renal cell carcinoma. Biochim Biophys Acta Rev Cancer, 2018. 1870(1): p. 23-31. Landolt2 7 .Buzhor, E., et al., Cell-based therapy approaches: the hope for incurable diseases. Regen Med, 2014. 9(5): p. 649-72. 2 8 . Chuang, C.H., et al., Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 2017. 23(3): p. 291-300.

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Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation

Cited by 32 publications

References 31 publications

Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

Histone methyltransferase and drug resistance in cancers

Molecular characterization of clonal human renal forming cells

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