2. Academic Validation
  3. A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer

A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer

  • Cell Death Dis. 2021 May 13;12(5):485. doi: 10.1038/s41419-021-03753-1.
Xuan Deng  # 1,  Fanyang Kong  # 2,  Si Li 3,  Haoqin Jiang 1,  Liu Dong 1,  Xiao Xu 1,  Xinju Zhang 1,  Hong Yuan 3,  Ying Xu 4,  Yimin Chu 4,  Haixia Peng 5,  Ming Guan 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
  • 2 Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, 222300, China.
  • 3 Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
  • 4 Digestive Endoscopy Center, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200050, China.
  • 5 Digestive Endoscopy Center, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200050, China. phx1101@shtrhospital.com.
  • 6 Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China. guanming@shmu.edu.cn.
  • # Contributed equally.
PMID: 33986248 DOI: 10.1038/s41419-021-03753-1
Abstract

Long noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal Cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL's role in conferring resistance to oxaliplatin-induced Apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.

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