Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

Abstract

The evolution of chemoresistance is a fundamental characteristic of cancer that ultimately defeats its clinical management. However, it may be possible improve patient outcomes significantly by defeating nodal resistance mechanisms which cancers rely upon during the evolution to an untreatable state.Here we report an essential role for upregulation of the stem cell reprogramming factor PBX1 in mediating chemoresistance in recurrent ovarian carcinomas. In clinical specimens, high levels of PBX1 expression correlated with shorter survival in post-chemotherapy ovarian cancer patients. In tumor cells with low endogenous expression of PBX1, its enforced expression promoted cancer stem cell-like phenotypes, including most notably an increase in resistance to platinum-based therapy used most commonly for management of this disease. Conversely, silencing PBX1 in platinum-resistant cells that overexpressed PBX1 sensitized them to platinum treatment and reduced their stem-likeproperties. An analysis of published genome-wide chromatin immunoprecipitation data indicated that PBX1 binds directly to promoters of genes involved in stem cell maintenance and the response to tissue injury. We confirmed direct regulation of one of these genes, STAT3, demonstrating that the PBX1 binding motif at its promoter acted to positively regulate STAT3 transcription. Pursing this connection, we determined that a STAT3/JAK2 inhibitor could potently sensitize platinum-resistant cells to carboplatin and suppress their growth in vivo. Our findings offer a mechanistic rationale to target the PBX1/STAT3 axis to defeat a key mechanism of chemoresistance in ovarian cancers and possibly other human cancers.3

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

“…5, we clearly demonstrated that c-Kit upregulates phospho-PHB Y259 in the lipid raft domain to interact with the membrane-tethered Notch3 fragment and enhance the Notch3-PBX1 signaling pathway in ovarian cancer cells. However, whether this increase in PBX1, a stem cell reprogramming factor in ovarian cancer chemoresistance [39], is Fig. 8 Downregulation of raft-phospho-PHB Y259 reduces tumorigenic ability and sensitizes tumors to carboplatin treatment.…”

“…Phospho-PHB Y259 in the membrane raft is required for the c-Kit-mediated activation of Notch3, PBX1, β-catenin and ABCG2 Activation of Notch signaling pathways might upregulate the downstream targets of Notch, such as PBX1, to drive the stemness and carcinogenesis of cancer [38,39]. We thus examined the effects of c-Kit on Notch3 and PBX1 in SKOV3 cells.…”

Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis

“…Therefore, there is no doubt that PBX1 promotes PCa cell proliferation, survival, and chemoresistance. Actually, a recent study showed that ovarian cancer chemoresistance relies on PBX1 overexpression (12). Our recent study has demonstrated that PBX1 promotes the expression of oncogenic RNF6, thus increasing leukemia chemoresistance to doxorubicin (3).…”

“…PBX1 has been demonstrated to confer to chemoresistance in both breast cancer (12) and leukemia (3), but it was not well known in PCa. To determine the expression profile of PBX1 in PCa, a panel of prostate tissues from patients with benign prostate hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), or primary PCa was evaluated by immunohistochemical (IHC) assays.…”

“…Although it is originally identified from pre-B leukemia cells (2), PBX1 is now also reported in other cancers such as lung, breast, and ovarian cancers to promote cancer cell proliferation, survival, and metastasis. PBX1 acts as a stem cell reprogramming factor in regulating long-term hematopoietic stem cells by maintaining their self-renewal and quiescence (20) but also driving stemness of ovarian cancer stem cells (12) and initiating leukemogenesis (21). It is also believed to be a pioneer factor promoting a transcriptional program favorable to breast cancer progression (22).…”