Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

Abstract

Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo. Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.

The Role and Mechanism of the Histone Methyltransferase G9a in Tumors: Update

“…Mechanistically, inhibiting histone methyltransferase eraser LSD1 and writer G9a induces cell death by S-phase arrest and apoptosis, targeting the endoplasmic reticulum (RS) stress pathway, thereby increasing this in-vitro and in-vivo effect. 29 …”

“…Mechanistically, inhibiting histone methyltransferase eraser LSD1 and writer G9a induces cell death by S-phase arrest and apoptosis, targeting the endoplasmic reticulum (RS) stress pathway, thereby increasing this in-vitro and in-vivo effect. 29 Hypoxia significantly increases the G9a protein level, which interacts with the Runt domain of RUNX3, increasing its methylation at K129 and K171, promoting cell cycle progression or division, and enhancing the growth of gastric cancer (GC) cells. G9a also inhibits immune responses and cell apoptosis, promoting early tumor growth.…”

Targeting Aberrant Histone Posttranscription Modification Machinery in Esophageal Squamous Cell Carcinoma: Current Findings and Challenges

“…Therefore, inhibiting more than one target simultaneously is a rational strategy. Junxia Min and colleagues found that inactivation of LSD1 with SP2509 and G9a using UNC0642 at the same time markedly suppressed the propagation in ESCC cells through functional screening an epigenetic library in a panel of cancer cell lines [ 12 ]. The authors demonstrated the potent synergistic effect of co-inhibiting LSD1 and G9a in ESCC cells as well as their tumor xenografts [ 12 ].…”

“…Junxia Min and colleagues found that inactivation of LSD1 with SP2509 and G9a using UNC0642 at the same time markedly suppressed the propagation in ESCC cells through functional screening an epigenetic library in a panel of cancer cell lines [ 12 ]. The authors demonstrated the potent synergistic effect of co-inhibiting LSD1 and G9a in ESCC cells as well as their tumor xenografts [ 12 ]. Additionally, the authors discovered that LSD1 and G9a are both deregulated in ESCC, and patients with high expression levels of both LSD1 and G9a had even significantly poor prognosis.…”

“…Additionally, the authors discovered that LSD1 and G9a are both deregulated in ESCC, and patients with high expression levels of both LSD1 and G9a had even significantly poor prognosis. All these data indicate that LSD1 and G9a are the potential targets for treating ESCC [ 12 ]. Interestingly, the authors showed that dual administration of the two drugs decreased the expression of several genes, such as PERK , ATF4 , CHOP , eIF2α , and ATF6 , implicated in ER stress, and targeting ER stress enhanced the sensitivity of ESCC cells to SP2509 and G9a treatment, which provided strong supporting evidence that targeting LSD1, G9a, and ER stress could serve as a promising strategy for clinical treatment of ESCC patients [ 12 ].…”