M6A demethylase ALKBH5 regulates FOXO1 mRNA stability and chemoresistance in triple-negative breast cancer
Xi Liu,
Pan Li,
Yuanfeng Huang,
Hongsheng Li,
Xin Liu,
Yaxi Du,
Xin Lin,
Danyang Chen,
Hao Liu,
Yongchun Zhou
Affiliations
Xi Liu
Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China; Cancer Center Office, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China
Pan Li
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
Yuanfeng Huang
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
Hongsheng Li
Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China
Xin Liu
Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China
Yaxi Du
Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China
Xin Lin
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
Danyang Chen
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
Hao Liu
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China; Corresponding author. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 78 Hengzhigang Rd, Guangzhou, Guangdong, 510095, China.
Yongchun Zhou
Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China; Cancer Center Office, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, 650118, China; Corresponding author. Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University, No.519 Kunzhou Road, Kunming, Yunnan, 650118, China.
Resistance to chemotherapy is the main reason for treatment failure and poor prognosis in patients with triple-negative breast cancer (TNBC). Although the association of RNA N6-methyladenosine (m6A) modifications with therapy resistance is noticed, its role in the development of therapeutic resistance in TNBC is not well documented. This study aimed to investigate the potential mechanisms underlying reactive oxygen species (ROS) regulation in doxorubicin (DOX)-resistant TNBC. Here, we found that DOX-resistant TNBC cells displayed low ROS levels because of increased expression of superoxide dismutase (SOD2), thus maintaining cancer stem cells (CSCs) characteristics and DOX resistance. FOXO1 is a master regulator that reduces cellular ROS in DOX-resistant TNBC cells, and knockdown of FOXO1 significantly increased ROS levels by inhibiting SOD2 expression. Moreover, the m6A demethylase ALKBH5 promoted m6A demethylation of FOXO1 mRNA and increased FOXO1 mRNA stability in DOX-resistant TNBC cells. The analysis of clinical samples revealed that the increased expression levels of ALKBH5, FOXO1, and SOD2 were significantly positively correlated with chemoresistance and poor prognosis in patients with TNBC. To our knowledge, this is the first study to highlight that ALKBH5-mediated FOXO1 mRNA demethylation contributes to CSCs characteristics and DOX resistance in TNBC cells. Furthermore, pharmacological targeting of FOXO1 profoundly restored the response of DOX-resistant TNBC cells, both in vitro and in vivo. In conclusion, we demonstrated a critical function of ALKBH5-mediated m6A demethylation of FOXO1 mRNA in restoring redox balance, which in turn promoting CSCs characteristics and DOX resistance in TNBC, and suggested that targeting the ALKBH5/FOXO1 axis has therapeutic potential for patients with TNBC refractory to chemotherapy.
