*5.2. Enhanced LUBAC Expression and Cancers*

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, and is subclassified into the germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes [137]. Patients with ABC-DLBCL usually have a worse prognosis than those with GCB-DLBCL, and oncogenic mutations in NF-κB signaling proteins, such as in the *CD79B*, *CARMA1*, *MYD88*, and *A20* genes, are associated with ABC-DLBCL. Staudt's group identified single nucleotide polymorphisms (SNPs) in human *HOIP* that cause the Q622L and Q584H substitutions, which are significantly associated with ABC-DLBCL [138]. Unexpectedly, these replacements, located in the UBA domain of HOIP, enhance the interactions with HOIL-1L and HOIP, resulting in the increased NF-κB activity. The authors developed stapled peptides, an α-helical short peptide with a hydrocarbon cross-link, targeting the HOIP-HOIL-1L interface, and demonstrated the suppressed viability of ABC-DLBCL cells. Indeed, the silencing of *HOIP* also reportedly reduces the viability of ABC-DLBCL cells [49]. Moreover, the E3s of c-IAP-1/2 are involved in ABC-DLBCL via the K63 ubiquitination of BCL10, which results in the recruitment of LUBAC and IKK to the CBM complex, thus inducing BCR-mediated NF-κB activation [139]. Therefore, SMAC mimetics, which lead to the autodegradation of c-IAP-1/2, block the growth of ABC-DLBCL cells. These results indicate that the enhanced LUBAC activity is associated with a poor prognosis in B cell lymphoma (ABC-DLBCL), and thus the inhibition of the LUBAC activity may be a valid therapeutic target.

Recently, Ruiz et al. showed that the expression of LUBAC subunits is enhanced in human and murine lung squamous cell carcinoma (LSCC) cells, but not adenocarcinoma cells, which results in the increased linear ubiquitination, NF-κB activation, and cisplatin-resistance in LSCC [140]. Moreover, the suppression of LUBAC activity, in addition to the suppression of TAK1, ameliorated the chemotherapy resistance of LSCC. Thus, LUBAC inhibitors seem to be therapeutic drug seeds to treat LSCC.
