KDM5B组蛋白去甲基化酶在许多癌症中过度表达，并在癌症发生中扮演着一个矛盾的角色，这取决于具体情境。这种矛盾性可以通过表达具有不同功能作用的KDM5B蛋白质同工异构体来解释，在各种癌细胞系中可能以不同水平存在。我们在这里展示了其中一个同工异构体，即KDM5B-NTT，由于与经典的PLU-1同型异构体相比具有明显的蛋白质稳定性，因此在乳腺癌细胞系中积累。该同工异构体是一个缩短的、催化不活性的mRNA产物，其转录起始位点位于PLU-1同型异构体的下游，因此使用了另一个ATG进行翻译起始。它也不同于PLU-1转录本，在包含一个先前被归因于其他假设的同工异构体的额外外显子（外显子6）中。在MCF7细胞中过表达该同工异构体会导致H3K4甲基化的增加，并诱导一个基因群的失抑制，包括肿瘤抑制剂Cav1和多个参与α-和γ-干扰素响应的基因。我们讨论了这一发现的相关性，考虑到KDM5B可能具有独立于其催化活性的调节作用的假设。©2023。作者。

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 a much 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.© 2023. The Author(s).