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Breast cancer (BC) figures as the most frequently diagnosed and the leading cause of cancer-related deaths among women worldwide. Despite considerable progress has been made in cancer detection and therapy assignment, several BCs become resistant to therapy and, moreover, a considerable proportion of patients develops metastasis during therapy or experiences relapse. Growing body of evidence indicates that alterations in tumour metabolism are linked to therapeutic resistance, tumour relapse and dissemination. These altered metabolic traits are caused by genetic alterations and environmental factors. The most frequently mutated gene in BC is the tumor suppressor TP53, a well-characterized transcription factor, which plays a central role in cellular homeostasis and prevention of tumour growth. In BC missense mutations occur very often in its DNA binding domain, providing neomorphic mutant p53 proteins that lose the wildtype onco-suppressive functions and acquire instead new oncogenic properties (Gain-of-Function). Indeed, mutant p53 proteins establish aberrant interactions with different transcription factors, thus inducing oncogenic transcriptional programs and metabolic reprogramming. Our previous work outlined a mutant p53 driven signature that promotes aggressiveness in BC in which DEP domain containing 1A (DEPDC1A) emerged as an important mediator of migration and invasiveness (Girardini et al., 2011). DEPDC1A expression is almost undetectable in normal cells, but it is overexpressed in different cancers and its overexpression is associated with poor prognosis. DEPDC1A is a transcriptional cofactor that exists in two different splice variants V1 and V2, but its role in oncogenesis, as well as in a physiological context, remains elusive. Here we show, through a high-throughput transcriptional analysis, that DEPDC1A is able to impinge on lipid metabolism. In particular we observed that mRNAs belonging to the fatty acids biosynthesis pathway genes ATP-Citrate Lyase (ACLY), Stearoyl-CoA Desaturase 1 (SCD1) and Elongation Of Very Long Chain Fatty Acids 6 (ELOVL6) were consistently downregulated upon DEPDC1A silencing suggesting a key role for this factor in controlling fatty acid metabolism in cancer cells. Indeed, ablation of DEDPC1A caused a significant decrease of lipid droplets content and fatty acid desaturation in MDA-MB-231 cell line. ACLY, SCD1 and ELOVL6, as a part of fatty acids biosynthesis pathway, are specific targets of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, master regulators of lipid metabolism. Interestingly, protein co-immunoprecipitation and Chromatin Immunoprecipitation assays demonstrated that DEPDC1A physically interacts with SREBP1 and that it is required for an efficient transcriptional activation of this particular subset of genes, thus acting as transcriptional cofactor of SREBP1. Finally, we showed that DEPDC1A, through SCD1 upregulation, is able to promote aggressive phenotypes, such as migration, and that DEPDC1A overexpression in normal cells is sufficient to induce sensitization toward SCD1 inhibition. This study unveils a novel oncogenic transcriptional program induced by the aberrant interaction between DEPDC1A and SREBP1 transcription factor that is able to induce fatty acid biosynthesis and desaturation in cancer cells and to establish a metabolic addiction that can be potentially exploited in cancer therapy.