Researchers at the Josep Carreras Leukaemia Research Institute (IJC) discover that a single molecular switch, HDAC7, controls both the development of healthy...

Histone deacetylase (HDAC) enzymes remove acetyl groups from acetyllysine-containing proteins, including nucleosomal histones to control gene expression. Beyond fundamental cell biology, HDAC activity is linked to various cancers, with many HDAC inhibitors developed as anticancer therapeutics. Among the 11 metal-dependent HDAC proteins, the four class IIa isoforms (HDAC4, 5, 7, and 9) are “pseudodeacetylases” without measurable enzymatic activity due to mutation of a catalytic tyrosine. Deacetylase-related activities of class IIa HDAC proteins are attributed to scaffolding functions, where recruitment of an active HDAC isoform leads to bound substrate deacetylation. Scaffolding of class IIa proteins beyond simple recruitment of an active HDAC is only starting to emerge. This review explores the various scaffolding roles of HDAC7, including recently reported acetylation-mediated reversible scaffolding, which is a form of acetyllysine-binding reader function. Studying the functional roles of HDAC7 will provide molecular insight into normal and pathological conditions, which could facilitate drug design.

STAT1 promotes ferroptosis and inflammation in hepatic ischemia-reperfusion injury by repressing miR-497-5p and activating HDAC7, revealing therapeutic targets for liver protection.

A new study published in The Journal of Immunology by researchers at the Josep Carreras Leukaemia Research Institute (IJC) has uncovered a crucial biological "off switch" in diffuse large B cell lymphoma (DLBCL), the most common and one of the most aggressive forms of blood cancer.

A new study published in The Journal of Immunology by researchers at the Josep Carreras Leukaemia Research Institute (IJC) has uncovered a crucial biological "off switch" in diffuse large B cell lymph...

Epigenetic suppression of branched-chain amino acid catabolism by HDAC7 promotes renal tumor progression.

A new study published in The Journal of Immunology by researchers at the Josep Carreras Leukaemia Research Institute (IJC) has uncovered a crucial biological "off switch" in diffuse large B cell lymphoma (DLBCL), the most common and one of the most aggressive forms of blood cancer. The findings reveal that a protein called HDAC7 plays a dual role: it is essential for building a healthy immune system, and when it goes missing in cancer cells, the disease becomes significantly more dangerous. Crucially, the team showed that restoring HDAC7 in cancer cells can slow or even stop tumor growth.

Glioblastomas (GBMs) are highly lethal brain tumors with limited treatment options and resistance to immune checkpoint inhibitors due to their immunosuppressive tumor microenvironment. Here, we identify OLIG2 as a key regulator of immune evasion in GBM stem-like cells, which inhibits CD8+ T cell–dependent antitumor immunity while promoting protumor macrophage polarization. Mechanistically, OLIG2 recruited HDAC7 to repress CXCL10 transcription, inducing STAT3 activation in tumor-associated macrophages (TAMs) and decreasing CD8+ T cell infiltration and activation. Genetic deletion of OLIG2 significantly increased CXCL10 secretion, shifting TAMs toward an antitumor phenotype and enhancing CD8+ T cell activities. Furthermore, upregulated OLIG2 expression was correlated with resistance to immune checkpoint inhibitors in patients with GBMs. OLIG2 inhibition by either genetic deficiency or pharmacological targeting with CT-179 sensitized GBM tumors to anti–PD-L1 therapy, enhancing antitumor immune responses and prolonging survival. Our findings reveal OLIG2+ glioma stem-like cells as critical mediators of immune evasion and identify the OLIG2/HDAC7/CXCL10 axis as a potential therapeutic target to enhance immune checkpoint inhibitor efficacy and improve immunotherapy outcomes in aggressive GBMs.

Class IIa histone deacetylases (HDACs) are a family of enzymes that despite their name, do not have