Journal article
Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells
Cancer discovery, Vol.12(2), pp.502-521
02/01/2022
DOI: 10.1158/2159-8290.CD-20-1848
PMCID: PMC8831451
PMID: 34615656
Abstract
Glioblastoma (GBM) is the most lethal primary brain cancer characterized by therapeutic resistance, which is promoted by GBM stem cells (GSC). Here, we interrogated gene expression and whole-genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated GBM cells (DGC), and neural stem cells (NSC) to identify master regulators of GSC stemness, revealing an essential transcription state with increased RNA polymerase II-mediated transcription. The YY1 and transcriptional CDK9 complex was essential for GSC survival and maintenance
and
. YY1 interacted with CDK9 to regulate transcription elongation in GSCs. Genetic or pharmacologic targeting of the YY1-CDK9 complex elicited RNA m
A modification-dependent interferon responses, reduced regulatory T-cell infiltration, and augmented efficacy of immune checkpoint therapy in GBM. Collectively, these results suggest that YY1-CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in GBM. SIGNIFICANCE: Effective strategies to rewire immunosuppressive microenvironment and enhance immunotherapy response are still lacking in GBM. YY1-driven transcriptional elongation machinery represents a druggable target to activate interferon response and enhance anti-PD-1 response through regulating the m
A modification program, linking epigenetic regulation to immunomodulatory function in GBM.
.
Details
- Title: Subtitle
- Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells
- Creators
- Zhixin Qiu - UPMC Hillman Cancer CenterLinjie Zhao - University of California, San DiegoJia Z Shen - Sanford Burnham Prebys Medical Discovery InstituteZhengyu Liang - University of California, San DiegoQiulian Wu - University of California, San DiegoKailin Yang - Cleveland ClinicLihua Min - UPMC Hillman Cancer CenterRyan C Gimple - University of California, San DiegoQiyuan Yang - Salk Institute for Biological StudiesShruti Bhargava - University of California, San DiegoChunyu Jin - University of California, San DiegoCheryl Kim - La Jolla Institute For Allergy & ImmunologyDenise Hinz - La Jolla Institute For Allergy & ImmunologyDeobrat Dixit - University of California, San DiegoJean A Bernatchez - University of California, San DiegoBriana C Prager - University of California, San DiegoGuoxin Zhang - University of California, San DiegoZhen Dong - University of California, San DiegoDeguan Lv - University of California, San DiegoXujun Wang - Center for Life SciencesLeo J Y Kim - Case Western Reserve UniversityZhe Zhu - University of California, San DiegoKatherine A Jones - Salk Institute for Biological StudiesYe Zheng - Salk Institute for Biological StudiesXiuxing Wang - University of California, San DiegoJair L Siqueira-Neto - University of MontanaLukas Chavez - University of California, San DiegoXiang-Dong Fu - University of California, San DiegoCharles Spruck - Sanford Burnham Prebys Medical Discovery InstituteJeremy N Rich - University of California, San Diego
- Resource Type
- Journal article
- Publication Details
- Cancer discovery, Vol.12(2), pp.502-521
- DOI
- 10.1158/2159-8290.CD-20-1848
- PMID
- 34615656
- PMCID
- PMC8831451
- ISSN
- 2159-8274
- eISSN
- 2159-8290
- Grant note
- R01 AI151123 / NIAID NIH HHS F30 CA217065 / NCI NIH HHS R35 CA197718 / NCI NIH HHS R01 AI107027 / NIAID NIH HHS P30 CA030199 / NCI NIH HHS P30 CA014195 / NCI NIH HHS P30 CA023100 / NCI NIH HHS F30 CA217066 / NCI NIH HHS S10 OD018499 / NIH HHS T32 GM007250 / NIGMS NIH HHS T32 CA094186 / NCI NIH HHS R01 NS103434 / NINDS NIH HHS R01 CA238662 / NCI NIH HHS
- Language
- English
- Date published
- 02/01/2022
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696714302771
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