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Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.

Cancer cell | 2020

Fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

Pubmed ID: 32531268 RIS Download

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA236399
  • Agency: NCI NIH HHS, United States
    Id: R50 CA211404
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK124116
  • Agency: NCI NIH HHS, United States
    Id: R01 CA214965
  • Agency: NCI NIH HHS, United States
    Id: R01 CA172558
  • Agency: NCI NIH HHS, United States
    Id: R01 CA169458
  • Agency: NCI NIH HHS, United States
    Id: R35 CA197628
  • Agency: NCI NIH HHS, United States
    Id: P30 CA033572
  • Agency: NCI NIH HHS, United States
    Id: R01 CA243386
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NCI NIH HHS, United States
    Id: T32 CA186895
  • Agency: NCI NIH HHS, United States
    Id: R01 CA213138
  • Agency: NCI NIH HHS, United States
    Id: R01 CA157644
  • Agency: NCI NIH HHS, United States
    Id: R01 CA211614
  • Agency: NCI NIH HHS, United States
    Id: U10 CA180827
  • Agency: NCI NIH HHS, United States
    Id: R01 CA137060

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Developmental Therapeutics Program (tool)

RRID:SCR_003057

Portal for preclinical information and research materials, including web-accessible data and tools, NCI-60 Tumor Cell Line Screen, compounds in vials and plates, tumor cells, animals, and bulk drugs for investigational new drug (IND)-directed studies. DTP has been involved in the discovery or development of more than 70 percent of the anticancer therapeutics on the market today, and will continue helping the academic and private sectors to overcome various therapeutic development barriers, particularly through supporting high-risk projects and therapeutic development for rare cancers. Initially DTP made its drug discovery and development services and the results from the human tumor cell line assay publicly accessible to researchers worldwide. At first, the site offered in vitro human cell line data for a few thousand compounds and in vitro anti-HIV screening data for roughly 42,000 compounds. Today, visitors can find: * Downloadable in vitro human tumor cell line data for some 43,500 compounds and 15,000 natural product extracts * Results for 60,000 compounds evaluated in the yeast assay * In vivo animal model results for 30,000 compounds * 2-D and 3-D chemical structures for more than 200,000 compounds * Molecular target data, including characterizations for at least 1,200 targets, plus data from multiple cDNA microarray projects In addition to browsing DTP's databases and downloading data, researchers can request individual samples or sets of compounds on 96-well plates for research, or they can submit their own compounds for consideration for screening via DTP's online submission form. Once a compound is submitted for screening, researchers can follow its progress and retrieve data using a secure web interface. The NCI has collected information on almost half a million chemical structures in the past 50 years. DTP has made this information accessible and useful for investigators through its 3-D database, a collection of three-dimensional structures for more than 200,000 drugs. Investigators use the 3-D database to screen compounds for anticancer therapeutic activity. Also available on DTP's website are 127,000 connection tables for anticancer agents. A connection table is a convenient way of depicting molecular structures without relying on drawn chemical structures. As unique lists of atoms and their connections, the connection tables can be indexed and stored in computer databases where they can be used for patent searches, toxicology studies, and precursor searching, for example.

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CD45.2-Biotin, mouse (antibody)

RRID:AB_2660733

This monoclonal targets CD45.2

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PE anti-human CD85k (ILT3) (antibody)

RRID:AB_2136645

This monoclonal targets CD85k

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PE anti-human CD86 (antibody)

RRID:AB_2721632

This monoclonal targets CD86

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Anti-rabbit IgG (H+L), F(ab) 2 Fragment (Alexa Fluor 555 Conjugate) (antibody)

RRID:AB_10694110

This unknown targets rabbit IgG (H+L) F(ab) 2 Fragment

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BV786 Mouse Anti-Human CD45 (antibody)

RRID:AB_2716864

This monoclonal targets CD45

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Normal Mouse IgG (antibody)

RRID:AB_145840

This polyclonal secondary targets not applicable

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β-Actin (8H10D10) Mouse mAb (antibody)

RRID:AB_2242334

This monoclonal targets beta-actin

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Goat Anti-Mouse IgG - H&L Polyclonal Antibody, HRP Conjugated (antibody)

RRID:AB_955439

This polyclonal targets Mouse Mouse IgG secondary - H&L

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Goat Anti-Rabbit IgG - H&L Polyclonal antibody, Hrp Conjugated (antibody)

RRID:AB_955447

This polyclonal targets Rabbit Rabbit IgG secondary - H&L

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GAPDH Antibody (0411) (antibody)

RRID:AB_627678

This monoclonal targets GAPDH

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FTO antibody [EPR6895] (antibody)

RRID:AB_10972698

This monoclonal targets FTO antibody [EPR6895]

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Anti-m6A (antibody)

RRID:AB_2279214

This polyclonal targets m6A

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5-Hydroxymethylcytosine (5-hmC) antibody (antibody)

RRID:AB_10013602

This polyclonal targets 5-Hydroxymethylcytosine (5-hmC)

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ZR-75-1 (cell line)

RRID:CVCL_0588

Cell line ZR-75-1 is a Cancer cell line with a species of origin Homo sapiens (Human)

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ML-2 (cell line)

RRID:CVCL_1418

Cell line ML-2 is a Cancer cell line with a species of origin Homo sapiens (Human)

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NOMO-1 (cell line)

RRID:CVCL_1609

Cell line NOMO-1 is a Cancer cell line with a species of origin Homo sapiens (Human)

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TF-1 (cell line)

RRID:CVCL_0559

Cell line TF-1 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MV4-11 (cell line)

RRID:CVCL_0064

Cell line MV4-11 is a Cancer cell line with a species of origin Homo sapiens (Human)

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U-937 (cell line)

RRID:CVCL_0007

Cell line U-937 is a Cancer cell line with a species of origin Homo sapiens (Human)

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B6.SJL-PtprcaPepc/BoyCrCrl (organism)

RRID:IMSR_CRL:564

Mus musculus with name B6.SJL-PtprcaPepc/BoyCrCrl from IMSR.

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NOD.Cg-Prkdcscid Il2rg/SzJ (organism)

RRID:IMSR_JAX:005557

Mus musculus with name NOD.Cg-Prkdcscid Il2rg/SzJ from IMSR.

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NOD.Cg-Rag1tm1Mom Il2rg Tg(CMV-IL3.CSF2.KITLG)1Eav/J (organism)

RRID:IMSR_JAX:024099

Mus musculus with name NOD.Cg-Rag1tm1Mom Il2rg Tg(CMV-IL3.CSF2.KITLG)1Eav/J from IMSR.

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MDA-MB-231 (cell line)

RRID:CVCL_0062

Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)

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NB4 (cell line)

RRID:CVCL_0005

Cell line NB4 is a Cancer cell line with a species of origin Homo sapiens (Human)

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Mono-Mac-6 (cell line)

RRID:CVCL_1426

Cell line Mono-Mac-6 is a Cancer cell line with a species of origin Homo sapiens (Human)

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K-562 (cell line)

RRID:CVCL_0004

Cell line K-562 is a Cancer cell line with a species of origin Homo sapiens (Human)

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Kasumi-1 (cell line)

RRID:CVCL_0589

Cell line Kasumi-1 is a Cancer cell line with a species of origin Homo sapiens (Human)

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THP-1 (cell line)

RRID:CVCL_0006

Cell line THP-1 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HEK293T (cell line)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

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