LXRα‐mediated downregulation of EGFR suppress colorectal cancer cell proliferation

Abstract

Liver X receptors (LXRs) are members of the nuclear receptor family, including the LXRα (NR1H3) and LXRβ (NR1H2) subtypes, which are related to the metabolism of glucose and cholesterol and possess anti‐inflammatory functions. Mounting evidence has linked LXRs to the inhibition of cell proliferation in a variety of cancers. We revealed a differential distribution for NR1H3, but not for NR1H2, in colorectal cancer and adjacent normal tissues. We found that NR1H3 enhanced the inhibitory action of GW3965, an agonist of LXRs, on the proliferation of colorectal cancer cells. Upregulation of NR1H3 enhanced the inhibition of cell proliferation by GW3965 while silencing of NR1H3 attenuated the inhibitory effect of GW3965 on cell proliferation. Bioinformatic prediction and luciferase assays showed that NR1H3 was able to inhibit the activity of the epidermal growth factor receptor (EGFR) promoter. Moreover, we demonstrated that activation of NR1H3 inhibited the growth of transplanted tumors in an animal experiment, with the inhibition accompanied by downregulation of EGFR. Our findings suggest that NR1H3 controls cell proliferation by affecting EGFR promoter activity. The high expression of EGFR was due to the downregulation of NR1H3 which is a novel molecular mechanism in the development of colorectal cancer.

EGFR/FOXO3A/LXR-α Axis Promotes Prostate Cancer Proliferation and Metastasis and Dual-Targeting LXR-α/EGFR Shows Synthetic Lethality

“…Liver X receptors, including LXR-α and LXR-β, are liganddependent nuclear receptors, which have more anti-proliferative effects on a variety of cancer cells (28)(29)(30)(31). Our results demonstrated that LXR-α had more anti-proliferative effects on prostate cancer cell lines than LXR-β (Figures 1, 2).…”

“…We also revealed a positive correlation between lower LXR-α levels and high-grade malignancy prostate cancer cell lines, and vice versa (Figures 1D,E). LXR-α has been implicated in growth regulation of a variety of cancer cells (28,47,48), but the regulation of prostate cancer cell growth has never been previously reported. Herein, we showed that LXR-α acts as a tumor suppressor in prostate cancer with the following lines of supporting evidence: (1) LXR-α is down-regulated in prostate cancer tissues and high levels of LXR-α predicts a biomarker for prostate cancer;…”

“…LXR-β is distributed ubiquitously, while LXRα is expressed highly in metabolically active cells/tissues such as the liver, macrophages, and adipose tissue (26). LXR agonists, such as T0901317 and GW3965, can not only reduce intracellular cholesterol content (27), but also activate LXRs and inhibit the proliferation of cancer cells (28)(29)(30)(31), including prostate cancer (32,33). In addition to enhanced de novo cholesterol synthesis (34), the cholesterol absorption process is also regulated by EGFR signaling activity (35).…”

“…Oncogenic transformation by EGFR increases the demand for cholesterol, and EGFR signaling antagonized LXR-α effects on cholesterol homeostasis (36). Furthermore, LXRs were significantly downregulated in tumor tissues and cells with an unknown mechanism (28,33).…”

The Expression of Methyltransferase-Like 3 in Oral Precancerous Lesions and Oral Squamous Cell Carcinoma

“…8 Several studies have reported that overexpression of METTL3 may promote tumor cell proliferation, migration, and the invasion of various solid tumors in vitro , such as gastric adenocarcinoma, and colorectal cancer. 10 11 In contrast, there were studies that showed the upregulation of METTL3, which could inhibit proliferation, migration, and invasion functions in colorectal cancer and renal cell carcinoma cells. 12 13 To date, a few studies have reported the expressions and possible roles of METTL3 in OSCCs.…”