Towards a molecular understanding of the overlapping and distinct roles of UBQLN1 and UBQLN2 in lung cancer progression and metastasis.

The Ubiquilin family of proteins (UBQLN) consists of five related proteins (UBQLN1-4 and UBQLNL) that all contain ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains. UBQLN1 and UBQLN2 are the most closely related and have been the most well-studied, however their biochemical, biological and cellular functions are still not well understood. Previous studies from our lab reported that loss of UBQLN1 or UBQLN2 induces epithelial mesenchymal transition (EMT) in lung adenocarcinoma cells. Herein, we showed that loss of UBQLN1 and/or UBQLN2 induces cellular processes involved in tumor progression and metastasis, including proliferation, clonogenic potential and migration in lung adenocarcinoma cells. In fact, following simultaneous loss of both UBQLN1 and UBQLN2 many of these processes were further enhanced. To understand the molecular mechanisms by which UBQLN1 and UBQLN2 loss could be additive, we performed molecular, biochemical and RNAseq analyses in multiple cellular systems. We identified overlapping and distinct gene sets and pathways that were altered following loss of UBQLN1 and/or UBQLN2. We have also begun to define cell type specific gene regulation of UBQLN1 and UBQLN2, as well as understand how loss of either gene can alter differentiation of normal cells. The data presented here demonstrate that UBQLN1 and UBQLN2 perform similar, but distinct molecular functions in a variety of cell types.