A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo

Abstract

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

“…Short-tandem repeat (STR) profiling, population doubling time, and cell morphology were always checked for the cells. The human prostate cancer tissues and matched adjacent normal prostate tissues of ten (10) written-informed consent castration-resistant prostate cancer (CRPC) patients were provided by Dr. Mi [ 17 ]. All protocols testing human cells/cells were approved by the Ethic Committee of Soochow University, in accordance to the principles expressed in the Declaration of Helsinki.…”

Identification of the mitochondrial protein POLRMT as a potential therapeutic target of prostate cancer

“…The expression levels of POLRMT in local prostate cancer tissues were explored as well. The prostate cancer tissues (“T”) and matched adjacent normal tissues (“N”) (provided by Dr. Mi [ 23 ]) from a set of ten (10) written-informed primary prostate cancer patients were tested. In the prostate cancer tissues, POLRMT mRNA expression was significantly higher than that in the normal tissues (Fig.…”

“…Next, the expression of POLRMT in different prostate cancer cells was examined as well. In patient-derived prostate cancer cells (“pCan1” and “pCan2”, from Dr. Mi [ 23 ]) and immortalized cell lines (PC-3/LNCaP), POLRMT mRNA expression is significantly higher than that in primary human prostate epithelial cells (“pEpi”, from Dr. Mi [ 23 ]) (Fig. 2E ).…”

“…The castration-resistant prostate cancer (CRPC) tissues and matched adjacent normal prostate epithelial tissues from ten written-informed consent primary patients were provided by Dr. Mi [ 23 ]. The protocols for testing human tissues were approved by the Ethics Committee of the First People’s Hospital of Taicang and were in according to the Declaration of Helsinki.…”

“…The primary human prostate cancer cells, “pCan1” and “pCan2”, deriving from two written-informed consent CRPC patients, as well as the primary human prostate epithelial cells (“pEpi”) were provided by Dr. Mi [ 23 ]. Cells were cultivated using the described protocols [ 24 ].…”