The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells.

Ziyu Zhang,Yibiao Yuan,Tianyi Zhang,Yuwen Zhu,Yong Xu,Xiaoling Zhang,Baoyu Chen

doi:10.3389/fcell.2021.664375

Abstract

The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.

Highlights

Despite the advancement in basic and clinical research and the development of sophisticated screening techniques and interventional regimens, breast cancer, especially in malignant forms, remains one of the leading causes for cancer-related deaths in female patients in the era of personalized medicine (Shieh and Tice, 2020)
Because the PIC assembly is acutely influenced by the chromatin status, we asked whether megakaryocytic leukemia 1 (MKL1) could impact differential histone modifications surrounding the RHOJ promoter region
We profiled the status of two well-documented histone modifications known to demarcate actively transcribed chromatin, acetylated H3 (H3Ac) and trimethylated H3K4 (H3K4Me3), and two for silenced chromatin, dimethylated H3K9 (H3K9Me2) and dimethylated H3K27 (H3K27Me2), surrounding the RHOJ promoter

Summary

Introduction

Despite the advancement in basic and clinical research and the development of sophisticated screening techniques and interventional regimens, breast cancer, especially in malignant forms, remains one of the leading causes for cancer-related deaths in female patients in the era of personalized medicine (Shieh and Tice, 2020). Malignant breast cancers are typically characterized by uncontrolled anchor-free growth, aggressive migration/invasion, acquisition of new genetic traits, and resistance to chemotherapeutic medications. These features that distinguish malignant breast cancers from more benign ones are mirrored by profound changes in cellular transcriptome (Parsons and Francavilla, 2019; Ding et al, 2020). Chen et al have found that, relying on singlecell RNA sequencing (scRNA-seq) data, a panel of conserved transcriptional events including those programmed by MYC and HIF-1α that help maintain stemness is likely the driving force behind malignant migration of breast cancer cells (Zhang et al, 2013). Transcriptomic analysis has led to the discovery that metabolic reprogramming skewing the cells toward oxidative phosphorylation from glycolysis may potentially contribute to breast cancer metastasis (Davis et al, 2020)

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