Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Abstract

Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates a-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKa-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT.

Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

“…Although it has been extensively reported that FH deficiency is associated to fumarate-dependent epigenetic deregulation, supporting the notion of FH as a tumor suppressor, the molecular mechanisms by which FH gene expression is controlled is not well clarified. It has been recently reported that in nasopharyngeal carcinoma, the chromatin remodeling factor lymphoid-specific helicase binds the FH promoter and recruits the epigenetic silencer factor G9a to inhibit the transcription of FH (213). The FH reduction promoted an unbalance in the TCA intermediates, with a decrease in malate levels and a concomitant increase in αKG amount.…”

“…The FH reduction promoted an unbalance in the TCA intermediates, with a decrease in malate levels and a concomitant increase in αKG amount. Deregulation of TCA metabolites in nasopharyngeal carcinoma cells induces the recruitment of IKKα to the promoter regions of genes involved in the EMT program, causing the downregulation of E-cadherin and ZO-1 and the parallel upregulation of the mesenchymal marker vimentin, leading to EMT, migration and invasion in vitro , and increase metastasis in vivo (213). …”

Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas

“…Interestingly, LSH-mediated CG methylation can modulate gene activity and influence neuron lineage commitment 21. Reports show that LSH contributes to the malignant progression of prostate cancer, melanoma, and nasopharyngeal carcinoma 20, 22, 23. However, the clinical significance of LSH in gliomas and which mechanism involved in the regulation of LSH remain poorly known.…”

RAF-MEK-MAPK Pathway Targeted by Tumor Suppression and Anticancer Therapeutic Agents

“…Previous study has shown that lymphoid-specific helicase (LSH), a SNF2-SWI chromatin remodeler, plays an essential role in cancer progression via regulation of fumarate hydratase (FH) [35]. Mechanistically, together with histone methyltransferase G9a, LSH is critical for the normal development of mammals and is involved in the establishment and maintenance of DNA methylation [36].…”

“…RASSF1A, the founding member of the RASSF family and RASSF5/NORE inhibits tumor growth and proliferation by targeting to signaling molecules of the MAPK family [23,35]. Phosphorylated ERK (pERK) is a key downstream component of the Ras/Raf/MEK/ERK signaling pathway.…”