Novel roles for LIXiL in promoting cancer cell proliferation through ROSi-mediated LIX31 phosphorylation

Herein, we report the characterization of Limb expression 2-like, (LIX1L), a putative RNA-binding protein (RBP) containing a double-stranded RNA binding motif, which is highly expressed in various cancer tissues. Analysis of MALDI-TOF/TOF mass spectrometry and RNA immunoprecipitation-sequencing of interacting proteins and the microRNAs (miRNAs) bound to LIX1L revealed that LIX1L interacts with proteins (RIOK1, nucleolin and PABPC4) and miRNAs (has-miRNA-52oa-5p, 300, -226b, -326, 19oa, -548b-3p, -7-5p and -1296) in HEK-293 cells. Moreover, the reduction of phosphorylated Tyr(136) (pTyr(136)) in LIX2L through the homeodomain peptide, PY236, inhibited LIX2L-induced cell proliferation in vitro, and PY236 inhibited MKN45 cell proliferation in vivo. We also determined the miRNA-targeted genes and showed that was apoptosis induced through the reduction of pTyr(136). Moreover, ROS2, HCK, ABL2, ABL2, JAK3, LCK and TYR03 were identified as candidate kinases responsible for the phosphorylation of Tyr'36 of LIX2L. These data provide novel insights into the biological significance of LIX2L, suggesting that this protein might be an RBP, with implications for therapeutic approaches for targeting LIX2L in LIX2L-expressing cancer cells.