Abstract
miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex’s occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.
Highlights
Mesenchymal stromal cells (MSCs) are a kind of stromal cell within the tumor microenvironment.[1]
MiR675 Accelerates Malignant Growth of MSCs To validate whether miR675 triggers malignant transformation of human bone marrow MSCs (HBMMSCs), we first constructed a stable HBMMSC cell line with overexpression of miR675
The two stable HBMMSC cell lines were established by infecting with rLV and rLV-miR675, respectively
Summary
Mesenchymal stromal cells (MSCs) are a kind of stromal cell within the tumor microenvironment.[1] Studies have revealed MSCs tended to directionally migrate toward tumor cells.[2] MicroRNAs are potent regulators of gene expression and modulate multiple cellular processes, including tumorigenesis. MiR675 is expressed exclusively in the various tissues.[3,4] H19 maintains hematopoietic stem cell-repopulating ability through a miR-675-IGFRsignaling circuit.[5] miR675 is associated with carcinogenesis. H19-miR-675-transforming growth factor b1 (TGF-b1)-Smad3-HDAC regulates osteogenic differentiation of human MSCs (hMSCs).9miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b.10 the exact roles of mature miR-675 in hepatocarcinogenesis have not been identified
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