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Last update 01 Nov 2024

PDL1 x KAT8 x IRF1

Last update 01 Nov 2024

Basic Info

Related Targets

PDL1KAT8IRF1

Drugs associated with PDL1 x KAT8 x IRF1

2142-R8 blocking peptide

Target

IRF1 x KAT8 x PDL1

Mechanism

IRF1 gene inhibitors [+2]

Active Org.

Sun Yat-Sen University

Originator Org.

Sun Yat-Sen University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PDL1 x KAT8 x IRF1

100 Translational Medicine associated with PDL1 x KAT8 x IRF1

0 Patents (Medical) associated with PDL1 x KAT8 x IRF1

Literatures (Medical) associated with PDL1 x KAT8 x IRF1

04 May 2023·Cancer discovery

Disruption of KAT8-IRF1 Condensate Formation Reduces PD-L1 Expression.

Article

The histone acetyltransferase KAT8 transcriptionally upregulates PD-L1 through cocondensation with IRF1.

Nature Cancer

Disrupting the phase separation of KAT8–IRF1 diminishes PD-L1 expression and promotes antitumor immunity

Article

Author: Zheng, Limin ; Zhang, Ruhua ; Zhang, Xia ; Kang, Tiebang ; Zhang, Nu ; Li, Ting ; Zhou, Penghui ; Zhou, Liwen ; Zheng, Lisi ; Zhang, Yijun ; Yu, Kuai ; Chen, Zhenxuan ; Wu, Yuanzhong ; Xu, Liping ; Zhang, Meifang ; Zou, Yezi ; He, Wenting

AbstractImmunotherapies targeting the PD-1/PD-L1 axis have become first-line treatments in multiple cancers. However, only a limited subset of individuals achieves durable benefits because of the elusive mechanisms regulating PD-1/PD-L1. Here, we report that in cells exposed to interferon-γ (IFNγ), KAT8 undergoes phase separation with induced IRF1 and forms biomolecular condensates to upregulate PD-L1. Multivalency from both the specific and promiscuous interactions between IRF1 and KAT8 is required for condensate formation. KAT8–IRF1 condensation promotes IRF1 K78 acetylation and binding to the CD247 (PD-L1) promoter and further enriches the transcription apparatus to promote transcription of PD-L1 mRNA. Based on the mechanism of KAT8–IRF1 condensate formation, we identified the 2142–R8 blocking peptide, which disrupts KAT8–IRF1 condensate formation and consequently inhibits PD-L1 expression and enhances antitumor immunity in vitro and in vivo. Our findings reveal a key role of KAT8–IRF1 condensates in PD-L1 regulation and provide a competitive peptide to enhance antitumor immune responses.

Nature Cancer

Biocondensates fuel tumor immune evasion

Article

Author: Quiroz, Felipe Garcia ; Kubelick, Kelsey P

A review.Transactivation hubs and related biomol. condensates are emerging as relevant mol. players in cancer biol.A new study now links PD-L1 upregulation on the cancer cell surface and IRF1-KAT8 transactivation hubs at PD-L1 loci.Therapeutic targeting of these hubs holds potential to unleash antitumor immunity.

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