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.
Transcriptional positive coactivator 4 (PC4) is a multifunctional nuclear protein that has important roles in DNA transcription, replication, repair and heterochromatinization. However, the role of PC4 in cancer remains to be clarified. Several studies propose that PC4 may act as a putative tumor suppressor. Here, we demonstrate for the first time that PC4 may represent a potential therapeutic target in non-small cell lung cancer (NSCLC). PC4 protein expression is significantly upregulated in NSCLC carcinoma tissues compared with their adjacent noncancerous counterparts as shown by immunohistochemical staining and western blotting in 104 pairs of formalin-fixed human NSCLC specimens and 6 fresh NSCLC samples. Knockdown of PC4 expression by sequence-specific small interfering RNA (siRNA) in human NSCLC cells (A549, H460 and H358) significantly inhibits the growth of cancer cells by the induction of cell cycle arrest and the increase of cell apoptosis in vitro. Interrupting the PC4 signaling pathway by injection of the PC4 siRNA liposome complex produced an effective regression of pre-established A549 cell xenografts in mice through growth inhibition and increased apoptosis. These results indicated that PC4 could be an attractive new therapeutic target for the treatment of NSCLC.
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