Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers

Abstract

A number of histone demethylases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human disease like cancer have not been well understood. Here, we demonstrate important roles of lysine-specific demethylase 1 (LSD1) in human carcinogenesis. Expression levels of LSD1 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (p < 0.0001). cDNA microarray analysis also revealed its transactivation in lung and colorectal carcinomas. LSD1-specific small interfering RNAs significantly knocked down its expression and resulted in suppression of proliferation of various bladder and lung cancer cell lines. Concordantly, introduction of exogenous LSD1 expression promoted cell cycle progression of human embryonic kidney fibroblast cells. Expression profile analysis showed that LSD1 could affect the expression of genes involved in various chromatin-modifying pathways such as chromatin remodeling at centromere, centromeric heterochromatin formation and chromatin assembly, indicating its essential roles in carcinogenesis through chromatin modification.Histone methylation plays important dynamic roles in regulating chromatin structure. Precise conformational regulation of chromatins is crucial for normal cellular processes such as DNA replication, DNA repair, chromosome recombination and mRNA transcription. Although histone methylation was considered to be a static modification until recently, the discovery of lysine-specific demethylase 1 (LSD1), which specifically demethylates mono-and dimethylated histone H3 at lysine 4 (H3-K4), indicated that the histone methylation was reversible.1 Subsequently, a JmjC domain-containing protein was identified to possess histone demethylase activity, and the JmjC domain was shown to be a demethylase signature motif.2 JmjC domain-containing enzymes catalyze the removal of methyl groups using a hydroxylation reaction, requiring iron and a-ketoglutarate cofactors. Several additional proteins were identified as histone lysine demethylases on the basis of the presence of the JmjC motif. 3-9 Although information of histone demethylases in their physiological function has been accumulated, their involvement in human disease remains unclear.We previously reported that SMYD3, a histone methyltransferase, stimulates cell proliferation through its methyltransferase activity and plays a crucial role in human carcinogenesis.10-14 Dysfunction of histone methylation was also shown to contribute to human carcinogenesis, 15-17 but the relationship between abnormal histone demethylation and human carcinogenesis is still largely unclear. To find demethylases involved in human carcinogenesis, we screened a number of histone demethylases in clinical tissues by expression profile analysis and found transactivation of LSD1 in various types of cancer.LSD1, also known as AOF2, is a histone demethylase that does not belong to the JmjC family, catalyzing the demethylation of histone H3-K4 and K9. LSD1 is composed of sever...

Histone onco-modifications

“…SMYD3, another H3K4 HMT, is highly expressed in cancer and seems to correlate with the development and progression of colorectal, hepatocellular and breast carcinoma (Hamamoto et al, 2004(Hamamoto et al, , 2006. Expression levels of LSD1, a HDM which removes H3K4me/me2 marks, are significantly elevated in bladder, lung, colorectal carcinoma and neuroblastoma (Schulte et al, 2009;Hayami et al, 2011). LSD1 expression correlates with adverse outcome and was inversely correlated with differentiation in neuroblastic tumors (Schulte et al, 2009).…”

LSD1-mediated epigenetic modification contributes to ovarian cancer cell migration and invasion

“…LSD1 is frequently overexpressed in lung cancer (5,6), breast cancer (7), prostate cancer (8,9), and liver cancer (10). Importantly, overexpression of LSD1 promotes the growth and invasion of various types of cancer cells, and contributes to human carcinogenesis by regulating the expression of genes involved in various chromatin-modifying pathways (6).…”

LSD1/CoREST is an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition

“…For example, this general, transferable concept is at the basis of the histone deacetylase inhibitors recently introduced for treatment of certain types of lymphomas (1,2). Lysine-specific demethylase-1 (LSD1 or KDM1A) is overexpressed in many solid tumors such as breast, colon, neuroblastoma, bladder, small cell lung, blood, and prostate cancers (3)(4)(5)(6)(7)(8)(9)(10)(11) and plays an important role in leukemia (12), attracting steadily increasing attention as a major target for epigenetic drug discovery (13,14).…”