MiR-153 promotes breast cancer cell apoptosis by targeting HECTD3

Am J Cancer Res. 2016 Jul 1;6(7):1563-71. eCollection 2016.


Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase which ubiquitinates caspase-8, caspase-9 and promotes cancer cell survival. Aberrant HECTD3 expression is frequently involved in various types of cancer progression. However, to date, the regulation of HECTD3 remains unclear. Here, we demonstrated that miR-153 functions as a negative regulator of HECTD3 and sensitizes cisplatin-induced apoptosis in triple-negative breast cancer cells MDA-MB-231 and BT-549. Luciferase reporter assay demonstrated that miR-153 suppresses HECTD3 expression through directly targeting its mRNA within the 3'-Untranslated Region (3'UTR). Additionally, the expression levels of miR-153 and HECTD3 are inversely correlated in breast cancer cell lines. Furthermore, ectopic expression of miR-153 promotes apoptosis in MDA-MB-231 and BT-549 cells treated with cisplatin or TNF-α, and miR-153 inhibitor treatment inhibits cisplatin induced apoptosis in MDA-MB-231 and BT-549 cells. Moreover, stable overexpression of HECTD3 abrogates the sensitization effect of miR-153 to cisplatin treatment in MDA-MB-231 cells, and miR-153 inhibitor protects cells against cisplatin cytotoxicity in control cells, but not in the stable knockdown HECTD3 MDA-MB-231 cells. More importantly, breast cancer patients with higher expression levels of miR-153 had significant higher 5-year survival rate in PROGmiR database (P<0.05). Taken together, our study indicated that miR-153 inhibits TNBC survival by targeting HECTD3 and functions as a potent tumor suppressor.

Keywords: HECTD3; apoptosis; miR-153.