LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem–like Cells

Abstract

Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decreases during differentiation. LSD1 was responsible for maintaining CSC self-renewal and tumorigenicity in HCC, and its overexpression was sufficient to drive self-renewal of non-CSC. Levels of acetylated LSD1 were low in CSC with high LSD1 activity, and these CSC were capable of self-renewal. Notch signaling activated LSD1 through induction of the sirtuin SIRT1, leading to deacetylation and activation of LSD1 and CSC self-renewal. Notably, we found that LSD1 expression was increased in cancer-associated fibroblasts (CAF) as an upstream driver of Notch3-mediated CSC self-renewal. In clinical specimens of HCC, the presence of CAF, LSD1, and Notch3 strongly associated with poor patient survival. Overall, our results reveal that CAF-induced expression of Notch3 is responsible for LSD1 activation in CSC, driving their self-renewal in HCC. These seminal findings illuminate a complex pathway in the tissue microenvironment of liver cancer, which is responsible for orchestrating the self-renewal of stem-like cancer cells, with potential implications to improve therapy and limit relapses. .

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

“…More recently, Liu et al confirmed several of the above results, including the contribution of high LSD1 levels to stemness and tumor growth, in a differently isolated HCC-CSC population (based on Nanog levels) [102]. Moreover, they investigated the regulation of LSD1 in HCC-CSCs and provided evidence that Notch signaling induced SIRT1 expression leading to LSD1 deacetylation, activation and stabilization.…”

“…Moreover, they investigated the regulation of LSD1 in HCC-CSCs and provided evidence that Notch signaling induced SIRT1 expression leading to LSD1 deacetylation, activation and stabilization. Finally, they provided in vivo evidence that the tumor microenvironment-through activated cancer-associated fibroblasts-stimulated Notch3 signaling, which, in turn, enhanced LSD1 expression to facilitate tumor growth [102].…”

CD44 standard isoform is involved in maintenance of cancer stem cells of a hepatocellular carcinoma cell line

“…It has been demonstrated that NOTCH2 is involved in self‐renewal of CSCs in HCC . NOTCH3 also reportedly regulates the stemness of CSCs of HCC . Although no functional relationship between CD44s and NOTCH3 in HCC has been reported, Ma Y, et al observed that NOTCH3 was upregulated in nonsmall cell lung cancer tissues from chemoresistant patients and was positively associated with CD44 .…”

Notch Signaling in the Tumor Microenvironment

“…In breast cancer, CAFs can also promote the cancer stem cell phenotype by secreting CCL2 (Tsuyada et al, 2012). Induction of Notch3 by CAFs is also associated with an increase in cancer stem cells in hepatocellular carcinoma (HCC) (Liu et al, 2017a). The Notchmediated interaction between cancer cells and the mesenchymal compartment is also involved in resistance to chemotherapy.…”