Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

Abstract

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.

Human positive coactivator 4 (PC4) is involved in the progression and prognosis of astrocytoma

“…PC4 expression is significantly increased in NSCLC specimens compared with their adjacent non-cancerous tissues [15]. Furthermore, the downregulation of PC4 markedly inhibited NSCLC cell proliferation in vitro, and A549 cell tumorigenicity in nude mice [15]. However, whether PC4 is involved in astrocytoma remains unclear.…”

“…Moreover, PC4 is one of the three genes that are amplified and upregulated in the SCLC cell lines [18]. PC4 expression is significantly increased in NSCLC specimens compared with their adjacent non-cancerous tissues [15]. Furthermore, the downregulation of PC4 markedly inhibited NSCLC cell proliferation in vitro, and A549 cell tumorigenicity in nude mice [15].…”

“…These results are consistent with previous findings. Peng et al [15] demonstrated that down regulation of PC4 markedly inhibited NSCLC cell proliferation. This inhibition was achieved through delaying the progression of cell cycle from G1 to S phase and triggering caspase-3-mediated apoptosis.…”

“…However, in contrast to serving as a potential tumor suppressor, PC4 has recently been recognized as a putative cancer promoter. Upregulated PC4 expression was reported in several cancers, including non-small cell lung cancer (NSCLC) [15], invasive intraductal papillary mucinous neoplasm of the pancreas [16], primary colorectal carcinomas [17] and small cell lung cancer (SCLC) cell lines [18]. Moreover, the knockdown of PC4 significantly inhibited the growth of cancer cells in NSCLC [15].…”

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

“…Expression of SUB1 was correlated with the levels of VEGF-C, VEGF-D and VEGFR-3 during the development of lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma. 33 SUB1 is also shown to play a role in non-small cell lung cancer (NSCLC) 34 and astrocytoma. 35 A recent study demonstrated that SUB1 plays a role in SMYD3 mediated transactivation of growth/invasion-stimulatory genes in cancer cells.…”