HDAC8 and STAT3 repress BMF gene activity in colon cancer cells

Abstract

Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to identify a direct target gene of HDAC8 repression, namely, BMF. Interestingly, the repressive role of HDAC8 could be uncoupled from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective inhibitors as therapeutic agents, beyond the reported involvement of HDAC8 in childhood malignancy.

HDAC8: a multifaceted target for therapeutic interventions

“…reported [59] (Figure 2). BMF has an important function in the execution of apoptosis triggered by the metabolite methylselenopyruvate, which is an inhibitor of HDAC8 [60].…”

“…smHDAC8 is the most abundant class I transcript, being expressed at high levels during almost all stages of the life cycle [69]. Transcript knockdown of smHDAC8 using RNAi in invasive [19,20,23,31,32,44,49,55,[57][58][59]; (B) muscle contraction [9]; and (C) entry of viruses [25]. (A) Representative molecular interactions of HDAC8 with crucial proteins in cancer.…”

“…(v) HDAC8 represses SOCS1/3 expression, which in turn enhances JAK2/STAT expression and cell growth [58]. (vi) HDAC8 interacts with STAT3 to repress BMF transcription [59]. (vii) HDAC8 regulates HOXA5 gene transcription to control p53 expression [19].…”

Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma

“…Although HDAC8 has been shown to promote growth of a number of cancer types (25), (37)(38)(39) and contribute to poor prognosis in childhood neuroblastoma (40), the molecular actions of HDAC8 in cancer remained poorly defined. Although specific HDACs can deacetylate nonhistone proteins (35), emerging data suggest that direct gene repression by HDAC8 might control key pathologic processes (41,42). Kang and colleagues have recently found that HDAC8 transcriptionally represses BMF, a Bcl-2 protein family member, to interfere BMF-mediated apoptosis in colon cancer cells (42).…”

“…Although specific HDACs can deacetylate nonhistone proteins (35), emerging data suggest that direct gene repression by HDAC8 might control key pathologic processes (41,42). Kang and colleagues have recently found that HDAC8 transcriptionally represses BMF, a Bcl-2 protein family member, to interfere BMF-mediated apoptosis in colon cancer cells (42). Our present data demonstrate that HDAC8 acts in concert with EZH2 to epigenetically silence the Wnt antagonists AXIN2, NKD1, PPP2R2B, and PRICKLE1, leading to b-catenin activation and consequential cell proliferation.…”