STAT3 induces G9a to exacerbate HER3 expression for the survival of epidermal growth factor receptor-tyrosine kinase inhibitors in lung cancers

Abstract

Background HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers. Methods First, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer. Results BBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study. Conclusions The present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.

PPARG Drives Molecular Networks as an Inhibitor for the Pathologic Development and Progression of Lung Adenocarcinoma

“…suppression of four LA promoters (IL1B, PTGS2, END1, and TNF) and stimulation of one LA inhibitors, MIR145. As an LA tumor cell suppressor [16], MIR145 was found to be involved in multiple other types of cancers, including breast cancer [17], colon cancer [18], and acute myeloid leukemia [19]. However, as shown in Figure 1, in the case of LA, the expression levels of MIR145 will be downregulated, which also got confirmed from the 13-LA-datasets mega-analysis (see PPARG_LA→Mega-analysis).…”

Histone methyltransferase and drug resistance in cancers

“…However, there was no answer on how to regulate HER3 to solve the problem of resistance. In 2019, Chang et al demonstrated that G9a inhibits miR-145-5p expression after catalyzing H3K9me2 and induces HER3 expression in tumor cells by RNAseq, gene manipulation and other technologies [67]. In addition, our team demonstrated that G9a promotes H3K9me2 and reduces H3K9ac in the PTEN promoter region, leading to PTEN transcriptional repression, which leads to activation of the AKT signaling pathway and promotes EGFR-TKI resistance [68].…”

STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells

“…Therefore, STAT3-upstream signals may be activated under regorafenib-induced stressful conditions [ 17 , 18 ], leading to STAT3 activation. Moreover, additive growth factors for tumorsphere formation, such as EGF and IL6, can phosphorylate STAT3 in cancer cells [ 9 , 13 , 19 ]. Thus, tumorspheres with constitutive STAT3 activation are expected to be resistant to regorafenib-inhibited cell growth.…”

“…STAT3 has been reported to both induce and repress microRNA expression [ 21 , 22 , 23 , 24 ]. One of the possible mechanisms might be the interaction of STAT3 with G9a and the epigenetic suppression of gene expression through methylation of H3K9, which thereby downregulate the expression levels of miR-200c and miR-145 [ 12 , 13 ]. Another methyltransferase (EZH2) is regulated by STAT3 and participates in anti-apoptosis in gastric cancer cells [ 25 ].…”

“…However, accumulated evidence indicates that STAT3 can repress the expression of microRNAs (miRNAs), short noncoding RNAs that repress post-transcriptional gene expression by binding to complementary sequences on the untranslated regions of targeted mRNAs, thus alternatively regulating gene expression. STAT3 can not only increase the expression levels of miRNAs in tumor cells [ 10 , 11 ] but also repress their levels (e.g., miR-200c and miR-145-5p) during cancer stem cell (CSC) growth [ 12 , 13 ]. Epigenetic regulation is considered as a strategy to rapidly respond to microenvironment stresses in tumors.…”