High expression of FOXM1 critical for sustaining cell proliferation in mitochondrial DNA-less liver cancer cells

• Published in: Experimental cell research Vol. 389; no. 1; p. 111889
• Main Authors: Higurashi, Masato, Maruyama, Tsuyoshi, Nogami, Yusuke, Ishikawa, Fumihiro, Yoshida, Yukiko, Mori, Kazunori, Fujita, Ken-ichi, Shibanuma, Motoko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2020
• Subjects: B-MYB; FOXM1; Hepatocellular carcinoma (HCC) cell line; Mitochondrial DNA copy number; OTUB1; PDT; mtDNA; Mitochondrial DNA copy number; Hepatocellular carcinoma (HCC) cell line; TUBEs; HCC; FOXM1; Dox; FOX; DUB; APC/C; SA-β-Gal; USP; TFAM; UPS; B-MYB; GD; EtBr; OTUB1
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2020.111889

The copy number of mitochondrial DNA (mtDNA) is decreased in most cancer types, including hepatocellular carcinoma (HCC), compared to normal counterparts. However, a decrease in mtDNA usually leads to defects in cell proliferation, which contradicts the robustness of cancer cell proliferation. In this study, we found that four out of seven HCC cell lines were of the mtDNA-less type. Interestingly, FOXM1, a member of the FOX transcription factor family, was highly expressed in a subset of them with proliferative potential maintained. B-MYB, a partner of FOXM1, was also expressed in the same cell lines. RNAi-mediated experiments demonstrated that when FOXM1/B-MYB was silenced in the cell lines, cell cycle-related genes were downregulated, while p21Cip1 was induced with senescence-associated β-galactosidase, resulting in G1/S cell cycle arrest. These results suggest that high expression of FOXM1/B-MYB is critical for sustaining cell proliferation in mtDNA-less cells. In addition, we found that high expression of FOXM1 was mediated by the deubiquitinating enzyme, OTUB1, in one cell line. Thus, interference with FOXM1/B-MYB expression, such as through OTUB1 inhibition, may induce a dormant state of senescence-like proliferation arrest in mtDNA-less cancer cells. This finding may be utilized for the development of precision medicine for relevant cancers. •Cell proliferation is deteriorated under mitochondrial DNA (mtDNA)-less conditions.•FOXM1 is highly expressed along with B-MYB in a subset of mtDNA-less HCC cell lines.•FOXM1/B-MYB is critical to overcome proliferative defects of mtDNA-less HCC cells.•Deubiquitination by OTUB1 contributes to high expression of FOXM1 in an HCC cell line.