Loss of SETD2‐mediated downregulation of intracellular and exosomal miRNA‐10b determines MAPK pathway activation and multidrug resistance in renal cancer

Abstract

SET domain‐containing 2 (SETD2) is the most frequently mutated gene among all the histone methyltransferases in clear cell renal cell carcinoma (ccRCC). Microarrays, RNA sequencing analysis and exosomes analysis of cellular supernatant were performed after transfection A498 cells with si‐SETD2 or siRNA of negative control. Chromatin immunoprecipitation and Luciferase reporter assay were conducted to evaluate the interaction between SETD2 and miR‐10b. Functional and drug experiments in vitro and in vivo were performed to verify the role of SETD2, miR‐10b and MAP4K4. The results showed that loss of SETD2 mediated downregulation of intracellular and exosomal microRNA‐10b. MAP4K4 were relevant to oncogenesis of ccRCC caused by loss of SETD2 and miR‐10b. SETD2 could directly target miR‐10b and regulate the expression of multidrug resistance (MDR)‐1 (P‐gp170) through JNK pathway, which was one of the downstream pathways of MAP4K4. The coordinated expression of SETD2/H3K36me3/miR‐10b/MAPKs/JNK/MDR pathway was revealed to the progression of ccRCC.

Prognostic and therapeutic roles of SETD2 in cutaneous melanoma

“…Studies have shown the loss of SETD2 influenced the inclusion of exons in genes known to be alternatively spliced and shifting in H3K36me3 signal, which leads to multidrug resistance. These data not just suggest a close relationship between trimethylation of H3K36 and RNA splicing, reflecting aberrant transcription or RNA processing [ 37 ], it also demonstrated the underlying mechanism of tumor-suppressor inactivation and multi-drug resistance via silencing SETD2 results in mRNA accumulation in the nucleus [ 38 ]. In our study, we found the significant correlation between SETD2 expression and RNA processing, we hypothesize that these pathways may be the underlying mechanisms by which the SETD2 dysfunction-related histone demethylation impacts on the survival and drug sensitivities.…”

Exosomes as novel tools for renal cell carcinoma therapy, diagnosis, and prognosis

“…Specifically, RCC-derived exosomes have been shown to induce apoptosis of T cells, inhibit the cytotoxic function of natural killer cells, and foster the expansion of immunosuppressive cell subsets such as regulatory T cells and myeloid-derived suppressor cells. Thereby, they create an immunosuppressive microenvironment, which is conducive to tumor growth [ 22 , [25] , [26] , [27] , [28] ]. Moreover, exosomes contribute to the metastatic cascade in RCC by orchestrating processes such as epithelial-mesenchymal transition (EMT) in tumor cells and preparing pre-metastatic niches in distant organs.…”