Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis

Abstract

Background: Autotaxin (ATX) is a secreted glycoprotein with the lysophospholipase D (lysoPLD) activity to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown. Results: In the present study, we demonstrated that trichostatin A (TSA), a well-known HDAC inhibitor (HDACi), significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSAinduced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis.

Autotaxin in Pathophysiology and Pulmonary Fibrosis

“…Moreover, a number of single nucleotide polymorphisms (SNPs) that associate with cancer susceptibility have been detected in or around ENPP2 ( 9 ). Promoter regions of ENPP2 were found hyper-methylated in primary invasive breast carcinomas ( 13 ), while inhibition of histone deacetylases 3 and 7 with trichostatin A also attenuated ENPP2 expression in colon cancer cells ( 14 ), suggesting that ENPP2 expression can be also amenable to epigenetic regulation. In mice, the highly (93%) homologous Enpp2 gene is located in chromosome 15 and has a similar structure ( 15 , 16 ).…”

Exocrine Pancreatic Carcinogenesis and Autotaxin Expression

“…ATX regulates levels of serum and tissue lysophosphatidic acids (LPA) which activates six receptors, out of which at least four (LPAR1 - 4) are expressed in human pancreatic tissue [49]. The physiological regulation of ATX is not well characterized, but a recent study indicates a role for histone deacetylators [50], and our present data thus indicate induction by xenobiotics. ATX inhibition results in a rapid decrease in e.g.…”

Autotaxin – A Target for the Treatment of Drug-Resistant Ovarian Cancer?

“…Indeed, autotaxin was first identified through its activity as an autocrine motility factor (Stracke et al 1992) and integrin 6 4 , which is associated with and invasive phenotype, can increase the expression of autotaxin (Chen and O'Connor 2005). Autotaxin and LPA promote the expression of the extracellular matrix protein osteopontin which promotes migration (Zhang et al 2011). Autotaxin activates the small G-proteins cdc42 and Rac (Jung et al 2002;Hoelzinger et al 2008;Harper et al 2010) and focal adhesion kinase (Jung et al 2002), proteins which are key regulators of cell motility.…”

“…Consequently, exposure to the HDAC inhibitor trichostatin (TSA) increases the expression of autotaxin and the subsequent production of LPA inhibits apoptosis induced by TSA. This suggests that autotaxin confers resistance to HDAC inhibitors (Li et al 2011). One clinical use of autotaxin inhibitors may be in combination with HDAC inhibitors.…”