Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

Yannick D. Benoit; Ryan R. Mitchell; Wenliang Wang; Luca Orlando; Allison L. Boyd; Borko Tanasijevic; Lili Aslostovar; Zoya Shapovalova; Meaghan Doyle; Christopher J. Bergin; Kinga Vojnits; Fanny L. Casado; Justin Di Lu; Deanna P. Porras; Juan Luis García-Rodriguez; Jennifer Russell; Aïcha Zouggar; Angelique N. Masibag; Cody Caba; Kalinka Koteva; Lakshmana K. Kinthada; Jagdish Suresh Patel; Sara N. Andres; Jakob Magolan; Tony J. Collins; Gerard D. Wright; Mickie Bhatia

doi:10.1016/j.chembiol.2021.04.014

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

Yannick D. Benoit, Ryan R. Mitchell, Wenliang Wang, Luca Orlando, Allison L. Boyd, Borko Tanasijevic, Lili Aslostovar, Zoya Shapovalova, Meaghan Doyle, Christopher J. Bergin, Kinga Vojnits, Fanny L. Casado, Justin Di Lu, Deanna P. Porras, Juan Luis García-Rodriguez, Jennifer Russell, Aïcha Zouggar, Angelique N. Masibag, Cody Caba, Kalinka KotevaLakshmana K. Kinthada, Jagdish Suresh Patel, Sara N. Andres, Jakob Magolan, Tony J. Collins, Gerard D. Wright, Mickie Bhatia

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Resumen

Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.

Idioma original	Inglés
Páginas (desde-hasta)	1394-1406.e10
Publicación	Cell Chemical Biology
Volumen	28
N.º	10
DOI	https://doi.org/10.1016/j.chembiol.2021.04.014
Estado	Publicada - 21 oct. 2021
Publicado de forma externa	Sí

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Benoit, Y. D., Mitchell, R. R., Wang, W., Orlando, L., Boyd, A. L., Tanasijevic, B., Aslostovar, L., Shapovalova, Z., Doyle, M., Bergin, C. J., Vojnits, K., Casado, F. L., Di Lu, J., Porras, D. P., García-Rodriguez, J. L., Russell, J., Zouggar, A., Masibag, A. N., Caba, C., ... Bhatia, M. (2021). Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics. Cell Chemical Biology, 28(10), 1394-1406.e10. https://doi.org/10.1016/j.chembiol.2021.04.014

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title = "Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics",

abstract = "Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.",

keywords = "SUMOylation, drug, leukemia, natural products, screening, selectivity, stem cells",

author = "Benoit, {Yannick D.} and Mitchell, {Ryan R.} and Wenliang Wang and Luca Orlando and Boyd, {Allison L.} and Borko Tanasijevic and Lili Aslostovar and Zoya Shapovalova and Meaghan Doyle and Bergin, {Christopher J.} and Kinga Vojnits and Casado, {Fanny L.} and {Di Lu}, Justin and Porras, {Deanna P.} and Garc{\'i}a-Rodriguez, {Juan Luis} and Jennifer Russell and A{\"i}cha Zouggar and Masibag, {Angelique N.} and Cody Caba and Kalinka Koteva and Kinthada, {Lakshmana K.} and Patel, {Jagdish Suresh} and Andres, {Sara N.} and Jakob Magolan and Collins, {Tony J.} and Wright, {Gerard D.} and Mickie Bhatia",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = oct,

day = "21",

doi = "10.1016/j.chembiol.2021.04.014",

language = "English",

volume = "28",

pages = "1394--1406.e10",

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Benoit, YD, Mitchell, RR, Wang, W, Orlando, L, Boyd, AL, Tanasijevic, B, Aslostovar, L, Shapovalova, Z, Doyle, M, Bergin, CJ, Vojnits, K, Casado, FL, Di Lu, J, Porras, DP, García-Rodriguez, JL, Russell, J, Zouggar, A, Masibag, AN, Caba, C, Koteva, K, Kinthada, LK, Patel, JS, Andres, SN, Magolan, J, Collins, TJ, Wright, GD & Bhatia, M 2021, 'Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics', Cell Chemical Biology, vol. 28, n.º 10, pp. 1394-1406.e10. https://doi.org/10.1016/j.chembiol.2021.04.014

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T1 - Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

AU - Benoit, Yannick D.

AU - Mitchell, Ryan R.

AU - Wang, Wenliang

AU - Orlando, Luca

AU - Boyd, Allison L.

AU - Tanasijevic, Borko

AU - Aslostovar, Lili

AU - Shapovalova, Zoya

AU - Doyle, Meaghan

AU - Bergin, Christopher J.

AU - Vojnits, Kinga

AU - Casado, Fanny L.

AU - Di Lu, Justin

AU - Porras, Deanna P.

AU - García-Rodriguez, Juan Luis

AU - Russell, Jennifer

AU - Zouggar, Aïcha

AU - Masibag, Angelique N.

AU - Caba, Cody

AU - Koteva, Kalinka

AU - Kinthada, Lakshmana K.

AU - Patel, Jagdish Suresh

AU - Andres, Sara N.

AU - Magolan, Jakob

AU - Collins, Tony J.

AU - Wright, Gerard D.

AU - Bhatia, Mickie

PY - 2021/10/21

Y1 - 2021/10/21

N2 - Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.

AB - Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.

KW - SUMOylation

KW - drug

KW - leukemia

KW - natural products

KW - screening

KW - selectivity

KW - stem cells

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DO - 10.1016/j.chembiol.2021.04.014

M3 - Article

C2 - 33979648

AN - SCOPUS:85117210820

SN - 2451-9456

VL - 28

SP - 1394-1406.e10

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 10

ER -

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

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