Nature Communications

Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma

K Konstantinos V. Floros C Carter K. Fairchild J Jinxiu Li K Kun Zhang J Jane L. Roberts R Richard Kurupi D Durga Paudel Y Yanli Xing B Bin Hu V Vita Kraskauskiene N Nayyerehalsadat Hosseini S Shanwei Shen M Melissa M. Inge K Kyllie Smith-Fry L Li Li A Afroditi Sotiriou K Krista M. Dalton A Asha Jose E Elsamani I. Abdelfadiel R Ronald D. Hill J Jamie M. Slaughter M Mayuri Shende M Madelyn R. Lorenz N Noritaka Tanaka T Taisuke Kajino M Mary L. Nelson M Mandy R. Hinojosa V Victor A. Kehinde B Benjamin R. Belvin F Febri G. Sugiokto Z Zhao Lai A Alexandros C. Dimopoulos S Sosipatros A. Boikos A Angeliki M. Stamatouli J Janina P. Lewis M Masoud H. Manjili H Hiromichi Ebi K Kristoffer Valerie R Renfeng Li A Andrew Poklepovic J Jennifer E. Koblinski T Trevor Siggers A Ana Banito M Mikhail G. Dozmorov K Kevin B. Jones S Senthil K. Radhakrishnan A Anthony C. Faber

Abstract

Abstract Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.

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Article Details

Volume / Issue Vol. 16, Issue 1
Published November 05, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (47)

K

Konstantinos V. Floros

C

Carter K. Fairchild

J

Jinxiu Li

K

Kun Zhang

J

Jane L. Roberts

R

Richard Kurupi

D

Durga Paudel

Y

Yanli Xing

B

Bin Hu

V

Vita Kraskauskiene

N

Nayyerehalsadat Hosseini

S

Shanwei Shen

M

Melissa M. Inge

K

Kyllie Smith-Fry

L

Li Li

A

Afroditi Sotiriou

K

Krista M. Dalton

A

Asha Jose

E

Elsamani I. Abdelfadiel

R

Ronald D. Hill

J

Jamie M. Slaughter

M

Mayuri Shende

M

Madelyn R. Lorenz

N

Noritaka Tanaka

T

Taisuke Kajino

M

Mary L. Nelson

M

Mandy R. Hinojosa

V

Victor A. Kehinde

B

Benjamin R. Belvin

F

Febri G. Sugiokto

Z

Zhao Lai

A

Alexandros C. Dimopoulos

S

Sosipatros A. Boikos

A

Angeliki M. Stamatouli

J

Janina P. Lewis

M

Masoud H. Manjili

H

Hiromichi Ebi

K

Kristoffer Valerie

R

Renfeng Li

A

Andrew Poklepovic

J

Jennifer E. Koblinski

T

Trevor Siggers

A

Ana Banito

M

Mikhail G. Dozmorov

K

Kevin B. Jones

S

Senthil K. Radhakrishnan

A

Anthony C. Faber

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