Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling

Abstract

Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5(+) HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5(+) cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5(+) CICs. Mechanistically, LSD1 promotes β-catenin activation by inhibiting the expression of several suppressors of β-catenin signaling, especially Prickle1 and APC in Lgr5(+) CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the β-catenin signaling is essential for maintaining the activity of Lgr5(+) CICs. Together, our findings unravel the LSD1/Prickle1/APC/β-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5(+) CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.

A directly negative interaction of miR-203 and ZEB2 modulates tumor stemness and chemotherapy resistance in nasopharyngeal carcinoma

“…Consistent with Ru's finding in breast cancer [26], miR-203 can significantly reduce the potential for chemotherapy resistance. It is well known that EMT and tumor stemness signals participate in chemotherapy resistance [27–29] We confirmed that miR-203 suppressed cell migration, invasion, tumor stemness, and DDP resistance by blocking EMT and stemness signal factors. This included downregulation of ZEB2, N-cadherin, BMI1, c-MYC, and NANOG, while inducing E-cadherin.…”

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

“…LGR5 was shown to increase drug resistance, and in colon primary tumors, LGR5-high expression correlated with chemoresistance and lower disease-free and overall survival (16,17,20,23,42,43). Thus, an LGR5-targeting ADC may not only effectively treat gastrointestinal tumors, but also function to eliminate CSCs.…”

“…CSCs can fuel tumor growth, confer resistance to standard chemotherapy and radiation, and are likely to contribute to recurrent disease (21). Correspondingly, high LGR5 expression in gastrointestinal tumors of different tissue types correlates with higher incidence of metastasis, drug resistance, and poor patient survival (16,(22)(23)(24). Thus, LGR5 may serve as an effective therapeutic target for the treatment of gastrointestinal cancers and CSC-based therapy.…”

Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC (Review)

“…Lei et al (117) used the lysine-specific demethylase 1A/prickle planar cell polarity protein 1/adenomatous polyposis coli/β-catenin signal axis as a novel molecular circuit to regulate the hepatocyte properties and chemoresistance of Lgr5 + LCSCs in liver, and the results confirmed that this signal axis may be used as a target for chemotherapy sensitization of liver cancer.…”