The product of the eleven–nineteen lysine-rich leukaemia (ELL) gene was first identified as a translocation partner of the mixed-lineage leukaemia (MLL) gene in acute myeloid leukaemia (AML). Subsequent studies identified ELL as a transcription elongation factor that could increase the rate of transcriptional elongation by RNA polymerase II in vitro, and later in vivo studies revealed its association with transcriptionally active loci.
In mammals, ELL is required for early embryogenesis12. Moreover, ELL has been identified as a partner of steroid receptors, hypoxia-inducible factor 1-alpha (HIF-1α), E2F1 and the TFIIH complex, modulating their binding partner’s activity.
The proto-oncogene, c-Myc, is frequently translocated in multiple myeloma and is highly amplified or mutated in many different human cancers. The c-Myc gene encodes a multifunctional transcription factor that plays important roles in regulating the expression of genes contributed to tumorigenesis, tumor maintenance as well as tumor metastasis. One of the most prominent mechanisms to degrade c-Myc is through the ubiquitin-proteasome pathway.
Fbw7 is the best studied E3 ubiquitin ligase for mediating c-Myc inhibition through degradation. Another RING-FINGER E3 ligase, Skp2, recognizes a conserved sequence element in the amino terminus of c-Myc (MBII) and HLH-LZ motifs (amino acids 367–439), promoting its poly-ubiquitination and degradation. The third RING-FINGER E3 ligase, β-TrCP, binds to the amino terminus of c-Myc and uses the UbcH5 ubiquitin-conjugating enzyme (E2) to form heterotypic polyubiquitin chains on c-Myc. The only homologous to E6-AP C-terminus (HECT) E3 ligase reported for c-Myc, HectH9, ubiquitinates c-Myc, forming a lysine 63-linked polyubiquitin chain, which does not trigger c-Myc degradation but, instead, is required for the transactivation of multiple target genes by c-Myc.
As one of the classic oncogenes, c-Myc is overexpressed in about 70% of human tumors; however, only 20% of these tumors exhibit c-Myc gene amplification or translocation. Thus, the deregulation of E3 ubiquitin ligase may contribute to the overexpression of c-Myc observed in human tumors. In fact, aberrant expression and/or mutation of some E3 ligases of c-Myc have been reported in tumours.
In this study, authors reveal a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc.
ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumor growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumor growth, but also promotes tumor metastasis.
Thus, this work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumor suppressor.
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