ELL (eleven-nineteen lysine-rich leukemia) was first identified as a translocation partner of MLL in acute myeloid leukemia. Increasing evidence supports that ELL is a key regulator of transcriptional elongation, participating in both the super elongation complex (SEC) and the little elongation complex (LEC) to regulate expression of HOX genes. In addition, ELL was reported to interact with steroid receptor, HIF-α and E2F1, and regulate their transcriptional activity. Due to early embryonic lethality in Ell-null mice, the physiological function of Ell in mammals remain elusive, and ELL has been widely reported as a transcriptional elongation factor.
Recently, Dr. XIAO Wuhan and his colleagues from Institute of Hydrobiology, Chinese Academy of Sciences (IHB) reported that ELL could interact directly with the pro-oncogene c-Myc, and function as an E3 ubiquitin ligase to accelerate the degradation of c-Myc, resulting the suppression of the growth of tumor. UbcH8 is the ubiquitin-conjugating enzyme in this pathway.
In addition, the cysteine 595 of ELL was identified as 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 suppresses c-Myc-dependent transcriptional activity and inhibits cell proliferation and 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.
This work not only reveals a previously unrecognized function for ELL as a novel E3 ubiquitin ligase for c-Myc, but also suggests a new clue to uncover the molecular mechanism of tumor metastasis. This work was recently published on Nature Communications with the title of “ELL targets c-Myc for proteasomal degradation and suppresses tumour growth”.
A model of ELL-mediated c-Myc degradation. UbcH8 transfers ubiquitin to C595 of ELL, after which ELL transfers ubiquitin from C595 to K51/52, K397 and K430 of c-Myc. After multiple cycles, ELL catalyzes the formation of K48-linked polyubiquitin chains at K51/52, K397 and K430 of c-Myc, which are recognized by the 26S proteasome and result in c-Myc degradation. (Figure by IHB)