MiR-129-5p is required for histone deacetylase inhibitor-induced cell death in thyroid cancer cells

Abstract

The molecular mechanism responsible for the antitumor activity of histone deacetylase inhibitors (HDACi) remains elusive. As HDACi have been described to alter miRNA expression, the aim of this study was to characterize HDACi-induced miRNAs and to determine their functional importance in the induction of cell death alone or in combination with other cancer drugs. Two HDACi, trichostatin A and vorinostat, induced miR-129-5p overexpression, histone acetylation and cell death in BCPAP, TPC-1, 8505C, and CAL62 cell lines and in primary cultures of papillary thyroid cancer (PTC) cells. In addition, miR-129-5p alone was sufficient to induce cell death and knockdown experiments showed that expression of this miRNA was required for HDACi-induced cell death. Moreover, miR-129-5p accentuated the anti-proliferative effects of other cancer drugs such as etoposide or human a-lactalbumin made lethal for tumor cells (HAMLET). Taken together, our data show that miR-129-5p is involved in the antitumor activity of HDACi and highlight a miRNA-driven cell death mechanism.

miR-886-3p Levels Are Elevated in Friedreich Ataxia

“…Interestingly a histone deacetylase inhibitor that has been shown to increase frataxin levels (Herman et al, 2006) caused decrease in the miR-886-3p levels. Histone deacetylase inhibitors have been shown previously to alter miRNA levels (Scott et al, 2006;Brest et al, 2011); however, this is the first link between HDAC inhibition and suppression of levels of miR-886-3p leading to enhanced frataxin expression (Fig. 3).…”

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“…For example, it has been demonstrated that miR-129-5p is required for histone deacetylase inhibitorinduced cell death in thyroid cancer cells [194]. Liu et al found that miR-129-5p suppressed tumor growth and reduced cell migration through inhibition of VCP (Valosin containing protein) in hepatocellular carcinoma [195].…”

Histone Deacetylase Inhibitors: A Novel Therapeutic Weapon Αgainst Medullary Thyroid Cancer?

“…Histone deacetylation allows DNA to wrap more tightly, thus becoming less accessible to the cell's transcription machine (1,7). More specifically, HDACs suppress the expression of tumor-suppressor genes and promote, in this way, the development and progression of tumors (13). In addition, HDAC activity is enhanced in both malignant and benign neoplasms (7).…”

“…What is more, they can sensitize tumor cells to radiation and chemotherapy (7) and make tumors more amenable to surgery (13). More specifically, HDACIs have been shown to synergize with antitumor/chemotherapy drugs, such as paclitaxel, cisplatin, etoposide, doxorubicin, the HAMLET protein complex, etc.…”

“…Of course, the most obvious effect of HDACIs is that the NH2 terminal of histones' lysine residues remains acetylated, which gives DNA a more open configuration. This is important as it allows key genes (e.g., tumor-suppressor genes) to be expressed (13).…”