The non-enzymatic RAS effector RASSF7 inhibits oncogenic c-Myc function.
Anbarasu KumaraswamyAnitha MamidiPavitra DesaiAnanthi SivagnanamLakshmi Revathi PerumalsamyChandrasekaran RamakrishnanMichael GromihaKrishnaraj RajalingamSundarasamy MahalingamPublished in: The Journal of biological chemistry (2018)
c-Myc 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 RASSF7 and c-Myc 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.
Keyphrases
- transcription factor
- binding protein
- endothelial cells
- cell proliferation
- poor prognosis
- protein protein
- amino acid
- gene expression
- rheumatoid arthritis
- genome wide
- wild type
- induced pluripotent stem cells
- cancer therapy
- genome wide identification
- minimally invasive
- nitric oxide
- squamous cell carcinoma
- signaling pathway
- papillary thyroid
- small molecule
- oxidative stress
- young adults
- hydrogen peroxide
- dna methylation
- long non coding rna
- idiopathic pulmonary fibrosis
- lymph node metastasis
- heat stress
- interstitial lung disease
- heat shock