Inhibiting an RBM39/MLL1 epigenomic regulatory complex with dominant-negative peptides disrupts cancer cell transcription and proliferation

Abstract

Inhibiting an RBM39/MLL1 epigenomic regulatory complex with dominant-negative peptides disrupts cancer cell transcription and proliferation Graphical abstract Highlights d A RBM39/MLL1 complex regulates H3K4me3 and gene expression in breast cancer d RBM39 recruits the MLL1 complex to regulate oncogene and tumor suppressor expression d Dominant-negative RBM39-derived peptides disrupt the RBM39/MLL1 complex d RBM39-derived peptides decrease cancer hallmarks in multiple breast cancer subtypes

hnRNPK-derived cell-penetrating peptide inhibits cancer cell survival

“…Our published work shows that a dominant-negative peptide derived from the RGG domain of SAFA (hnRNPU) has effects on cancer cell survival, histone marks, and other key processes that are similar to those of CPP-hnRNPK-RGG. 42 , 43 Despite the similarity in structure between the RGG domain of hnRNPK and hnRNPU and those of other hnRNPs, peptides derived from the RGG domains of hnRNPA1 and hnRNPF had no effect on survival of the cancer cells we tested. It could be that these hnRNPs have more limited roles in cancer cells and/or that their RGG domains have molecular functions different from those of hnRNPK and hnRNPU.…”

“…However, many of these interventions are directed at molecules and processes that are also required in normal cells, resulting in significant toxicity. We have shown that dominant-negative peptides derived from the RNA-binding domains of hnRNPU and RBM39 (also known as CAPERα) have minimal effects on normal cells because they disrupt cancer-cell-specific interactions and molecular functions 42 , 43 and may have significant clinical advantages over less targeted approaches. Here, we provide support for further exploration and development of a peptide with dominant-negative functions in hnRNPK, called CPP-hnRNPK-RGG, as a therapeutic peptide.…”

“… 41 We recently developed novel RBM39- and hnRNPU-derived dominant-negative CPPs that reduce the survival and proliferation of a range of cancer cells. 42 , 43 We have demonstrated that RBM39-derived CPPs disrupt its interaction with the MLL1 complex and its DNA targets, while a peptide derived from the RGG domain of SAFA (also known as hnRNPU) disrupts its interaction with target RNAs. In both cases, the resulting effects on the epigenetic landscape, transcription, and splicing decrease the growth and survival of multiple types of cancer cells while leaving normal cells unharmed.…”

Systematic pan‐cancer analysis identifies RBM39 as an immunological and prognostic biomarker

“… 17 Another study reported that RBM39 acts as a major transcriptional regulator and interacts with the MLL1 complex to promote breast cancer cell proliferation. 18 In patients with hepatocellular carcinoma, RBM39 was first identified as an autoantigen whose overexpression reduced tumour angiogenesis and growth and inhibited v‐Rel‐mediated lymphocyte transformation. 19 , 20 , 21 Previous studies have shown that RBM39 is involved in biological processes in colorectal adenocarcinoma development, such as cell survival and anchoring non‐dependent growth.…”

“…RBM39 is a coactivator of ER, ER, and Activator Protein‐1 (AP‐1) component c‐Jun, which binds transcription and mRNA precursor processing together and effectively boosts their transcriptional activity, hence encouraging breast cancer growth 17 . Another study reported that RBM39 acts as a major transcriptional regulator and interacts with the MLL1 complex to promote breast cancer cell proliferation 18 . In patients with hepatocellular carcinoma, RBM39 was first identified as an autoantigen whose overexpression reduced tumour angiogenesis and growth and inhibited v‐Rel‐mediated lymphocyte transformation 19–21 .…”