HDAC5–LSD1 axis regulates antineoplastic effect of natural HDAC inhibitor sulforaphane in human breast cancer cells

Abstract

Our recent studies have shown that cross-talk between histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) facilitates breast cancer progression. In this work, we demonstrated that regulatory activity at -356 to -100 bp promoter element plays a critical role in governing HDAC5 transcription. By using DNA affinity precipitation and mass spectrometry, we identified a group of factors that bind to this element. Among these factors, Upstream Transcription Factor 1 (USF1) was shown to play a critical role in controlling HDAC5 transcription. Through screening a panel of epigenetic modifying drugs, we showed that a natural bioactive HDAC inhibitor, sulforaphane, downregulated HDAC5 transcription by blocking USF1 activity. Sulforaphane facilitated LSD1 ubiquitination and degradation in an HDAC5-dependent manner. A comparative microarray analysis demonstrated a genome wide cooperative effect of HDAC5 and LSD1 on cancer-related gene expression. shRNA knockdown and sulforaphane inhibition of HDAC5/LSD1 exhibited similar effects on expression of HDAC5/LSD1 target genes. We also showed that coordinated cross-talk of HDAC5 and LSD1 is essential for the antitumor efficacy of sulforaphane. Combination treatment with sulforaphane and a potent LSD1 inhibitor resulted in synergistic growth inhibition in breast cancer cells, but not in normal breast epithelial cells. Furthermore, combined therapy with sulforaphane and LSD1 inhibitor exhibited superior inhibitory effect on MDA-MB-231 xenograft tumor growth. Taken together, our work demonstrates that HDAC5-LSD1 axis is an effective drug target for breast cancer. Inhibition of HDAC5-LSD1 axis with sulforaphane blocks breast cancer growth and combined treatment with LSD1 inhibitor improves the therapeutic efficacy of sulforaphane.

Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade

“…Moreover, multiple lines of evidence showed that adaptive resistance to anti-PD1 therapy is mediated by the PI3K/Akt pathway in cancer (50, 51). Our recent microarray has shown that inhibition of LSD1 increases the expression of Fas and down-regulates of PI3K/Akt signaling (52). Future work is needed to determine whether inhibition of LSD1 enhances therapeutic efficacy of immune checkpoint blockade through regulation of activities of Fas and PI3K/Akt signaling in TNBC.…”

Targeting histone lysine-specific demethylase KDM1A/LSD1 to control epithelial-mesenchymal transition program in breast cancers

“…Current clinical trials utilizing epigenetic drugs for combination therapy have been shown to be promising in treating metastatic cancers. Vasilatos et al [52] suggest that the combination therapy of LSD1 and HDAC inhibitors leads to expression activation of genes such as E-cadherin in Triple-negative breast cancer (TNBC) [52][53][54] . More recently, Yang et al [55] proposed that LSD1 interacts with SIN3A/HDAC complex, which plays a role in EMT-induced cancer stemness inhibiting a series of genes, such as TERT (Telomerase reverse transcriptase), CUL4A (Cullin4A), TGFB2 (Transforming growth factor beta 2 ), MDM2 (Mouse double minute 2 homolog ), RHOA (Ras homolog family member A) and HIF-1α [55] .…”

Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers

“…SFN treatment blocks the upstream transcription factor 1 (USF1) of HDAC5 inhibits the breast cancer cell lines. SFN with LSD1 inhibitor selectively inhibit the growth of cancer cell [ 101 ]. Withaferin A (WA), a metabolite derived from Withania somnifera and SFN promote breast cancer cell death by decreasing the BCL-2 and increasing the Bax expression [ 102 ].…”