The long non-coding RNA (lncRNA) SPRIGHTLY (formerly SPRY4-IT1), which lies within the intronic region of the SPRY4 gene is upregulated in human melanoma cells compared to melanocytes. SPRIGHTLY regulates a number of cancer hallmarks including proliferation, motility, and apoptosis. To better understand its oncogenic role, SPRIGHTLY was stably transfected into human melanocytes, which resulted in increased cellular proliferation, colony formation, invasion, and development of a multinucleated dendritic-like phenotype. RNA sequencing and mass spectrometric analysis of SPRIGHTLY-expressing cells revealed changes in the expression of genes involved in cell proliferation, apoptosis, chromosome organization, regulation of DNA damage responses, and cell cycle. The proliferation marker Ki67, minichromosome maintenance genes (MCM2-5), the anti-apoptotic gene X-linked inhibitor of apoptosis (XIAP) and the baculoviral IAP repeat-containing 7 (livin) were all upregulated in SPRIGHTLY-expressing melanocytes, while the pro-apoptotic tumor suppressor gene DPPIV/CD26 was downregulated, followed by an increase in ERK 1/2 phosphorylation, suggesting an increase in MAPK activity. Since downregulation of DPPIV is known to be associated with malignant transformation in melanocytes, SPRIGHTLY-mediated DPPIV downregulation may play an important role in melanoma pathobiology. Together, these findings provide important insights into how SPRIGHTLY regulates cell proliferation and anchorage-independent colony formation in primary human melanocytes.