A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression - Article

Sep 24, 2026

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KDM5B histone demethylase shows context-dependent roles in oncogenesis, potentially driven by isoform-specific expression. The study identifies KDM5B-NTT as a truncated, catalytically inactive product that accumulates in breast cancer cell lines due to higher protein stability than the canonical PLU-1 isoform. KDM5B-NTT increases bulk H3K4 methylation and derepresses a gene cluster, including Cav1 and interferon-alpha/gamma response genes, supporting regulatory functions beyond enzymatic activity.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Introduction

Histone methylation and KDM classes

Roles of KDM5 enzymes in transcriptional regulation

KDM5B in cancer and tissue-specific expression

[www.nature.com/cgt](www.nature.com/cgt) Cancer Gene Therapy ARTICLE OPEN A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression Elena Di Nisio 1,2, Valerio Licursi 3, Cecilia Mannironi 3, Valentina Buglioni 1, Alessandro Paiardini 4, Giulia Robusti 5, Roberta Noberini5, Tiziana Bonaldi5,6 and Rodolfo Negri 1,3 ✉ © The Author(s) 2023 | | | | | --- | --- | --- | | | KDM5B histone demethylase is overexpressed in many cancers and plays an ambivalent role in oncogenesis, depending on the speciﬁc context. This ambivalence could be explained by the expression of KDM5B protein isoforms with diverse functional roles, which could be present at different levels in various cancer cell lines. We show here that one of these isoforms, namely KDM5B-NTT, accumulates in breast cancer cell lines due to remarkable protein stability relative to the canonical PLU-1 isoform, which shows amuch faster turnover. This isoform is the truncated and catalytically inactive product of an mRNA with a transcription start site downstream of the PLU-1 isoform, and the consequent usage of an alternative ATG for translation initiation. It also differs from the PLU-1 transcript in the inclusion of an additional exon (exon-6), previously attributed to other putative isoforms. Overexpression of this isoform in MCF7 cells leads to an increase in bulk H3K4 methylation and induces derepression of a gene cluster, including the tumor suppressor Cav1 and several genes involved in the interferon-alpha and-gamma response. We discuss the relevance of this | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | ﬁnding considering the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity. | | | | | Cancer Gene Therapy (2023) 30:822–832; [https://doi.org/10.1038/s41417-022-00584-w](https://doi.org/10.1038/s41417-022-00584-w) | | | | | | INTRODUCTION Histone methylation is a dynamic modiﬁcation that is tightly controlled during cellular differentiation by the coordinated key action of histone methyltransferases and demethylases [1] . Histone lysine demethylases (KDMs) act as both readers and erasers of this modiﬁcation. Speciﬁcally, there are two enzymatic classes of histone demethylases in human: the FAD-dependent amine oxidases, belonging to the lysine-speciﬁc histone demethylase (LSD) family, also known as the KDM1 subfamily, and the Fe(II) and 2-oxoglutarate-dependent oxygenases with a conserved JmjC catalytic domain, belonging to the Jumonji histone demethylases (JHDMs) family, also known as the KDM2-KDM7 subfamilies [2, 3] . KDMs show a high level of substrate speciﬁcity, with each acting on speciﬁc lysine residues with different degrees of methylation. Histone methylation may lead to different transcriptional outcomes, such as gene activation or repression, depending on the residue involved, the degree of methylation, and the location of the mark in the genome [4, 5] . Among the KDMs, KDM5 (or JARID1) enzymes act on H3K4me2/me3, playing an important role in transcriptional regulation, especially during development and differentiation. KDM5 enzymes can act as epigenetic repressors by removing the transcriptional activating mark H3K4me3 at gene promoter regions, but they can also act as transcriptional activators by removing H3K4me3 from the body of actively transcribed genes to safeguard transcriptional elongation by repressing spurious intragenic transcription [6] . Moreover, they can contribute to transcriptional activation by converting H3K4me3 to H3K4me1 at enhancer regions, as H3K4me1 modiﬁcation combined with acetylated H3K27 is predictive of active enhancers. KDM5 proteins are also involved in DNA doublestrand break repair [7, 8] and chemoresistance [9–11] . The mammalian KDM5 subfamily consists of KDM5A (also known as JARID1A or RBP2), KDM5B (als

FAQs

What is KDM5B-NTT and why does it accumulate in breast cancer cells?

KDM5B-NTT is a truncated, catalytically inactive KDM5B isoform. It accumulates because it has remarkable protein stability compared with the canonical PLU-1 isoform, which shows faster turnover.

How does KDM5B-NTT affect histone marks and gene expression?

Overexpression of KDM5B-NTT in MCF7 cells increases bulk H3K4 methylation and induces derepression of a gene cluster. This cluster includes the tumor suppressor Cav1 and genes involved in interferon-alpha and interferon-gamma responses.

Why might KDM5B regulate cancer-related processes without catalytic activity?

The findings suggest that KDM5B may have regulatory roles independent of its catalytic activity. This is supported by the effects produced by a catalytically inactive isoform.

Sep 24, 2026

Uploaded by Ophelia