The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has shown promising efficacy in limited preclinical studies. We used a panel of human ERMS and ARMS cell lines and xenografts to evaluate the effects of SAHA as a therapeutic agent in both RMS subtypes. SAHA decreased cell viability by inhibiting S-phase progression in all cell lines tested, and induced apoptosis in all but one cell line. Molecularly, SAHA-treated cells showed activation of a DNA damage response, induction of the cell cycle inhibitors p21 Cip1 and p27 Kip1 and downregulation of Cyclin D1. In a subset of RMS cell lines, SAHA promoted features of cellular senescence and myogenic differentiation. Interestingly, SAHA treatment profoundly decreased protein levels of the driver fusion oncoprotein PAX3-FOXO1 in ARMS cells at a post-translational level. In vivo, SAHA-treated xenografts showed increased histone acetylation and induction of a DNA damage response, along with variable upregulation of p21 Cip1 and p27 Kip1. However, while the ARMS Rh41 xenograft tumor growth was significantly inhibited, there was no significant inhibition of the ERMS tumor xenograft RD. Thus, our work shows that, while SAHA is effective against ERMS and ARMS tumor cells in vitro, it has divergent in vivo effects. Together with the observed effects on the PAX3-FOXO1 fusion protein, these data suggest SAHA as a possible therapeutic agent for clinical testing in patients with fusion protein-positive RMS.

HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts

“…We hereby demonstrate that treatment of young AG04431 HDFs with SAHA induces cell proliferation arrest (as detected by a decreased staining of Ki-67 in these cells), concomitant with an increased protein abundance of p21 WAF-1 , an increase in the proportion of SA-βgal positive cells, a decreased expression of Lamin B1 and an increased expression and secretion of several SASP factors. These results concur with the induction of biomarkers of senescence, including growth arrest, following SAHA treatment in human leukemia cell lines [ 39 ], in rhabdomyosarcoma cell lines [ 40 ] and in human colon cancer cell line HCT116 [ 41 ]. As p21 WAF-1 protein abundance is increased at 24 hr after SAHA treatment, it could be involved in the early proliferative arrest.…”

Histone Deacetylase Expressions in Hepatocellular Carcinoma and Functional Effects of Histone Deacetylase Inhibitors on Liver Cancer Cells In Vitro

“…Moreover, we observed that SAHA but not TSA promoted features of cellular senescence in HCC cells. In some tumors such as rhabdomyosarcoma [44] and urothelial carcinoma [45], HDAC inhibition has been shown to affect senescence. Fan.…”

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

“…Different HDACis have been found to induce senescence; however, the clinical implication is not yet fully understood. In rhabdomyosarcoma, vorinostat was shown to mediate senescent features and increase the expression of the cell cycle inhibitors p21 and p27 [ 113 ]. Urothelial cancer cells revealed senescence morphologies upon treatment with unselective HDACis [ 114 ].…”