The non-enzymatic RAS effector RASSF7 inhibits oncogenic c-Myc function

Abstract

is a proto-oncogene controlling expression of multiple genes involved in cell growth and differentiation. Although the functional role of c-Myc as a transcriptional regulator has been intensively studied, targeting this protein in cancer remains a challenge. Here, we report a trimodal regulation of c-Myc function by the Ras effector, Ras-association domain family member 7 (RASSF7), a nonenzymatic protein modulating protein-protein interactions to regulate cell proliferation. Using HEK293T and HeLa cell lines, we provide evidence that RASSF7 destabilizes the c-Myc protein by promoting Cullin4B-mediated polyubiquitination and degradation. Furthermore, RASSF7 competed with MYC-associated factor X (MAX) in the formation of a heterodimeric complex with c-Myc and attenuated its occupancy on target gene promoters to regulate transcription. Consequently, RASSF7 inhibited c-Myc-mediated oncogenic transformation, and an inverse correlation between the expression levels of the and genes was evident in human cancers. Furthermore, we found that RASSF7 interacts with c-Myc via its RA and leucine zipper (LZ) domains and LZ domain peptide is sufficient to inhibit c-Myc function, suggesting that this peptide might be used to target oncogenic c-Myc. These results unveil that RASSF7 and c-Myc are functionally linked in the control of tumorigenesis and open up potential therapeutic avenues for targeting the "undruggable" c-Myc protein in a subset of human cancers.

TAK1 Phosphorylates RASSF9 and Inhibits Esophageal Squamous Tumor Cell Proliferation by Targeting the RAS/MEK/ERK Axis

“…Of these proteins, RASSF9 is known to play critical roles in tumor cell physiology. [24,25,27] Based on the mass spectra data ( Figure S10A,B, Supporting Information), serine residue at 284 (S284) in RASSF9 was found to be phosphorylated. Interestingly, this site is highly conserved among RASSF9s from different species ( Figure S10C, Supporting Information).…”

Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results

“…This finding is consistent with the previous reports of misexpression of genes involved in central nervous system development in suicide 14,46 . In addition, we identified a significant correlation with DNA methylation for the expression of genes involved in processes contributing to remodelings in the central nervous system, such as RASSF7 involved in cell proliferation and cytoskeletal organization 47,48 ; CTNND1 and MBP, which have been implicated in cell adhesion and migration 49 ; and MBP, which encodes for a major constituent of the myelin sheath of oligodendrocytes 50 . Furthermore, the NKX6-2 gene has shown to have an important role in the generation of cortical interneurons and their differentiation 51 .…”

Regulation of RASSF by non-coding RNAs in different cancers: RASSFs as masterminds of their own destiny as tumor suppressors and oncogenes

“…RASSF7 promoted E3 ligase Cullin-4B-mediated ubiquitylation and proteasomal degradation of c-Myc [ 35 ]. CUL4B protein levels were noted to be reduced in RASSF7-depleted cancer cells.…”

“…However, RASSF7 abolished c-Myc- driven binding of the co-activator TRRAP to the promoter regions of the target genes. Furthermore, RASSF7 also impaired formation of heterodimeric complexes between c-Myc and Max [ 35 ].…”