NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer

Abstract

Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis and triple-negative breast cancer (TNBC) when comparing breast cancers to one another. Here we show that in almost all cases, when comparing breast tumors to adjacent normal ducts, PTEN expression is decreased and the PRC2-associated methyltransferase EZH2 is increased. We further find that when comparing breast cancer cases in large cohorts, EZH2 inversely correlates with PTEN expression. Within the highest EZH2 expressing group, NOTCH alterations are frequent, and also associate with decreased PTEN expression. We show that repression of PTEN occurs through the combined action of NOTCH (NOTCH1 or NOTCH2) and EZH2 alterations in a subset of breast cancers. In fact, in cases harboring NOTCH1 mutation or a NOTCH2 fusion gene, NOTCH drives EZH2, HES-1, and HEY-1 expression to repress PTEN transcription at the promoter, which may contribute to poor prognosis in this subgroup. Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

“…In addition, the fact that PI3K/Akt activity was dependent not only on the Gβγ component but also on Ras, which is overactivated by gainof-function mutation in PDAC, was confirmed by the results that 5-HT 7 KD or treatment with inhibitor (SB-269970) maintained PI3K/Akt-dependent NF-κB nuclear translocation and EZH2 expression level. Moreover, our study confirmed that EZH2 KD, but not TPH1-5-HT 7 KD, induced an increase in the expression of DAB2IP and PTEN, which inhibit Ras and PI3K, respectively [34][35][36][37]. These results demonstrate that once EZH2 is expressed, it performs a master regulatory action on intracellular signaling pathways through two directions, (1) activation of PI3K/Akt and JAK2/STAT3 through transactivation of TPH1-5-HT 7 expressions, and (2) supporting PI3K/Akt activity by inhibition of the signals that inhibit PI3K/Akt through downregulation of DAB2IP and PTEN (Figure 8).…”

“…To reveal this difference, we examined whether the gene transcriptional repression action of EZH2 is linked to these signaling pathways. We found that EZH2 KD increased expression of DAB2IP and PTEN ( Figure 4 D), which are known to inhibit Ras and PI3K, respectively [ 34 , 35 , 36 , 37 ].…”

The long and short non-coding RNAs modulating EZH2 signaling in cancer

“…Breast cancer is one of the most encountered malignancies among women with miRNAs and EZH2 playing a significant role in proliferation, metastasis, and therapy response [ 146 , 147 ]. This section is dedicated to discussing miRNA and EZH2 interaction in breast cancer cells.…”

Roles of transducin-like enhancer of split (TLE) family proteins in tumorigenesis and immune regulation

“…On the other hand, AML oncogenic events promote cell proliferation and disrupt the terminal differentiation of myeloid cells, both of which are required for AML development. Frontiers in Cell and Developmental Biology frontiersin.org through the HES1 and TLE complex and the recruitment of HDACs (Wong et al, 2012;Pappas et al, 2021;Zhang et al, 2022). PTEN inhibition consequently enhances PI3K/Akt signaling activation and promotes the survival of T-ALL cells (Wong et al, 2012;Pappas et al, 2021;Zhang et al, 2022).…”