ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Abstract

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor- (AR-) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

ONECUT2 upregulation is associated with CpG hypomethylation at promoter‐proximal DNA in gastric cancer and triggers ACSL5

“…If ACSL5 is a downstream target of OC2 , as shown in our present study, one would expect that its activity can be inhibited by modulation of OC2 . In a mouse model of metastatic prostate cancer, OC2 was shown to be inhibited by CSRM617, a newly identified small molecule . Additionally, we confirmed a positive correlation between CDX2 , OC2 and ACSL5 expression in 311 gastric tumor tissues (Supporting Information Fig.…”

“…In our study, we demonstrated that OC2 acquired aberrant gain of function in GC as a consequence of specific epigenetic alterations and promoted GC cell proliferation and tumor growth in vitro and in vivo , thus suggesting that OC2 plays an important role during the acquisition of some hallmark capabilities in a variety of human cancers including GC. In addition, OC2 mRNA is a urine biomarker for the detection of PC, and a risk‐associated genetic variant in prostate cancer patients has been associated with OC2 activity, and OC2 acts as a master regulator and survival factor in aggressive prostate cancer variants . Moreover, OC2 is also a target for the microRNA miR‐429 or miR‐9, downregulation of which is associated with OC2 activation, which may contribute to the development of hepatocellular carcinoma or colorectal cancer …”

“…Although a role for OC2 in cancer is not well defined, it was recently reported that OC2 is associated with the development of colorectal cancers . More recent work showed that OC2 is hyperactivated in a substantial subset of human prostate cancers and therefore is a potential drug target for the metastatic phase of aggressive prostate cancers . The biological role, if any, of OC2 in GC has not yet been examined.…”

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…One cut homeobox 2 (ONECUT2), a transcription factor, is highly overexpressed in a number of human malignancies including prostate and lung cancer [188][189][190][191]. Overexpression of ONECUT2 in RAS-driven lung adenocarcinoma promotes tumor growth and invasion [191].…”

Epigenetic modulations and lineage plasticity in advanced prostate cancer

“…The authors also showed that treatment with a small molecule inhibitor, CSRM617, against ONECUT2 has promising effects in prostate cancers. 89 Kim et al 90 reported that PEG10 is highly expressed in NEPC. Targeting PEG10 reduces proliferation rate and expression of neuroendocrine markers.…”