Cancer metabolism and epigenetic alteration, especially in chromatin remodeling, are two critical mechanisms for carcinogenesis, however, the dynamic interplay between them in tumors remains poorly understood. Lymphocyte-specific helicase (LSH), a member of the ATP-dependent helicase in sucrose nonfermenting 2 (SNF2), is not only involved in DNA methylation, but it also promotes RNA polymerase II stalling. Epithelial-mesenchymal transition (EMT) is thought to be activated in cancer cells, linked to their dissociation from the primary tumor and their intravasation into blood vessels. However, the effect of EMT in cancer progression, especially in chromatin remodeling, remains poorly understood. Oncoprotein latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus (EBV) infects more than 90% of the global adult population and contributes to several malignancies, including nasopharyngeal carcinoma (NPC).We here provide robust evidence that LSH is highly expressed in NPC, where it is controlled by LMP1.Furthermore, we found that LSH does not only promote growth, migration, and invasion of NPC cancer cells in vitro, but also links with EMT, including cell migration, invasion, and tumor growth and colonization in vivo, indicating that LSH plays a critical role in tumor growth and metastasis through promoting transition from the epithelial stage to the mesenchymal stage. Then we found a repressive regulatory role of LSH in the expression of fumarate hydratase (FH) expression. a key component of the TCA cycle, catalyzes the hydration of fumarate to malate and is essential for cellular energy production and macromolecular biosynthesis. We confirmed that LSH is an important regulator of FH expression and down-regulates FH protein level in NPC derived from xenograft and clinical samples. We found that LSH was associated with the fh promoter; therefore, FH may serve as a direct target of LSH function. However, LSH may repress the fh promoter independent of DNA methylation, indicating that another mechanism is involved. G9a, also known as euchromatic histone-lysine N-methyltransferase 2, is an important epigenetic regulator, which monomethylates and dimethylates lysine-9.We provided the evidence of an interaction between LSH and G9a; the evidence of recruitment of G9a to the fh promoter in a LSH-dependent manner; and the evidence of subsequent chromatin modification leading to FH promoter repression, thus linking epigenetic regulation by LSH with suppression of the emerging tumor suppressor gene FH. Then, we found further that TCA cycle intermediates and the ratio of a-KG/succinate and a-KG/fumarate are regulated by LSH, However, we found no association between the EBV status and the intermediates of TCA cycles in NPC patients. Moreover, TCA intermediates promote cancer progression through the decrease of epithelial markers and the increase of mesenchymal marker expression. Finally, we demonstrate that the chromatin regulator and transcriptional activator inhibitor of nuclear factor kappa-B kinase alpha (IKKa) may be involved in the regulation of EMT markers, mediating the effect of LSH and TCA intermediates. LSH overexpression, as well as de-regulation of TCA intermediates, leads to IKKa recruitment to the promoters of EMT-related genes. In this way, LSH induces a cascade of epigenetic and metabolic changes that result in further epigenetic regulations via IKKa and EMT.