Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor

Abstract

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

Gene modification by fast‐track recombineering for cellular localization and isolation of components of plant protein complexes

“…CAF1 and ASF1 play a pivotal role in the deposition of histone H3/4 core during DNA replication and are involved in the regulation of DNA repair, recombination, endoreduplication, epigenetic imprinting, heterochromatin silencing and cell fate determination (Cheloufi and Hochedlinger, ; Jiang and Berger, ). Among other candidates of H3.1‐interactors (Figure , Table S3), the PHD finger protein (AT4G23860) was identified as a homologue of human histone H3‐binding UBR7 E3 ubiquitin ligase, which mediates K120 ubiquitination of histone H2B and acts as breast cancer tumour suppressor (Kleiner et al ., ; Adhikary et al ., ). The tetratricopeptide repeat protein NASP (AT4G37210) was identified as a member of conserved H3‐binding SHNi‐TRP domain factors that mediate deposition of H3‐variants in yeast and Arabidopsis (Dunleavy et al ., ; Maksimov et al ., ), while the DNA‐J chaperones ATJ6 and AT3G12170 were found to be closely related to the human nuclear H3‐binding factor DNAJC9 (Campos et al ., ; Lambert et al ., ).…”

Manumycin Polyketides Act as Molecular Glues Between UBR7 and P53 to Impair Breast Cancer Pathogenicity

“…Our data currently suggest that the asukamycin-mediated phenotypes and effects upon TP53 activity are independent of ubiquitination functions of UBR7. However, we cannot exclude the normal functional role of UBR7 in conferring anti-cancer activity of asukamycin 37,52,54 . Further work will be critical in better understanding the role of UBR7 and cancer.…”

“…While UBR7 is annotated as an E3 ubiquitin ligase and postulated to be involved in histone ubiquitination 37 , its biochemical and physiological functions are poorly understood especially with regard to cancer cell proliferation. We attempted to reconstitute the activity of UBR7 in vitro, but our various efforts to demonstrate UBR7 activity failed.…”

Cdh4 Down-Regulation Impairs in Vivo Infiltration and Malignancy in Patients Derived Glioblastoma Cells

“…This cells/neurites guidance activity seems at least in part due to the combinatorial cadherins expression that during development generates a molecular code allowing cell sorting and fasciculation based on preferential cadherin homophilic dimerization [21,42,43]. The Cdh4 role in cancer is still less clear since in some studies it seems to have oncogenic properties [29,32] maintaining stemness features and increasing tumor cell migration and malignancy, while in other cases it acts as an oncosuppressor since its dowregulation increases malignancy in different tumor types [27,28,30,31]. These contrasting results can be due to different functions performed by Cdh4 in different tumor types.…”

“…Moreover, Cdh4 expression seems important for tumorigenesis in different tumor types. However, the role of this molecule has not been fully clarified yet, since in some tumors it promotes malignancy while in other it acts as a tumor suppressor [27,28,29,30,31,32].…”