Higd-1a regulates the proliferation of pancreatic cancer cells through a pERK/p27KIP1/pRB pathway. (1st October 2019)

• Record Type: Journal Article
• Authors: An, Hyun-Jung; Ryu, Mihyeun; Jeong, Hye Jin; Kang, Minho; Jeon, Hyung-Min; Lee, Jie-Oh; Kim, Young Sang; Lee, Hayyoung
• Is Part Of: Cancer letters. Volume 461(2019)
• Page Start: 78
• Page End: 89
• Publication Date: 2019-10-01
• Subjects: HIMP1-a -- HIG1 -- Oncogene -- Cell cycle -- Senescence; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.07.007
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Higd-1a/HIMP1-a/HIG1, a mitochondrial inner membrane protein, promotes cell survival under low glucose and hypoxic conditions. We previously reported that it interacts with Opa1, a factor involved in mitochondrial fusion, to regulate mitochondrial homeostasis. In the present study, we found that depletion of Higd-1a inhibited the proliferation of pancreatic cancer cells in vitro and in mice xenografts. Higd-1a knockdown did not itself lead to cell death but it caused cell cycle arrest through induction of p27 KIP1 and hypo-phosphorylation of RB protein. Knockdown of Higd-1a also induced cellular senescence as shown by increased granularity and SA-β-galactosidase activity. We further showed that the mitochondrial stress induced by Higd-1a led to reduced ERK phosphorylation. Inhibition of the ERK pathway with U0126 induced p27 KIP1 expression in the pancreatic cancer cells, confirming that the cell cycle retardation was the result of inhibition of the ERK pathway. Array analysis of human pancreatic cancers revealed that expression of Higd-1a was significantly elevated in pancreatic cancer tissues compared to normal tissue. Collectively, our results demonstrate that Higd-1a plays an important role in the proliferation of pancreatic cancer cells by regulating the pERK/p27 KIP1 /pRB signaling pathway. Highlights: Higd-1a expression is up-regulated in human pancreatic tumor tissue. Higd-1a depletion inhibited cancer cell growth in vitro and in mouse xenografts. This growth retardation resulted from the regulation of the pERK/p27KIP1/pRB pathway. Higd-1a-depleted cells displayed the characteristics of senescence.