Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency

Abstract

Neuroendocrine differentiation (NED) frequently occurs in androgen-deprivation therapy (ADT)-resistant prostate cancer (PCa) and is typically associated with metabolic pathway alterations, acquisition of lineage plasticity, and malignancy. There is no conventional therapeutic approach for PCa patients with NED pathologic features because the molecular targets are unknown. Here, we evaluated the regulatory mechanism of NED-associated metabolic reprogramming induced by ADT. We detected that the loss of the androgen-responsive transcription factor, zinc finger, and BTB domain containing 10 (ZBTB10), can activate pyruvate kinase L/R (PKLR) to enhance a NED response that is associated with glucose uptake by PCa cells. PKLR exhibits a tumor-promoting effect in PCa after ADT, but ZBTB10 can compensate for the glucose metabolism and NED capacity of PKLR through the direct transcriptional downregulation of PKLR. Targeting PKLR by drug repurposing with FDA-approved compounds can reduce the aggressiveness and NED of ADT-resistant PCa. We demonstrated that PKLR acts as a modulator to activate NED in PCa enhancement by loss of ZBTB10, thereby enabling PCa cells to mount a glycolysis response essential for therapeutic resistance. Our findings highlight the broad relation between NED and metabolic dysfunction to provide gene expression-based biomarkers for NEPC treatment.

Intermittent Hypoxia Promotes TAM-Induced Glycolysis in Laryngeal Cancer Cells via Regulation of HK1 Expression through Activation of ZBTB10

“…Through the intersection analysis of transcription factors targeting HK1 and DEGs, ZBTB10 was screened out as the differently expressed transcription factor targeting HK1 (Figure 7A). It has been reported that ZBTB10 is involved in pyruvate kinase metabolism, which is a key process of the glycolysis response essential for cancer progression [28]. The RNA-seq results also revealed that the expression of the transcription factor ZBTB10 was elevated, and we confirmed that ZBTB10 mRNA and protein expression levels were elevated in both Hep2 and TU686 cells treated with conditioned medium, consistent with the RNA-seq results (Figure 7B-E).…”

Immunosuppressive role of BDNF in therapy‐induced neuroendocrine prostate cancer

“…Our previous report has demonstrated the upregulation of neuroendocrine marker expression in androgen‐dependent LNCaP cells treated with long‐term MDV3100 [ 41 , 42 ]. Our findings are consistent with other studies that used the same cells under similar culture conditions [ 43 ].…”

R-loop resolution by ARIP4 helicase promotes androgen-mediated transcription induction

“…S2C) is supportive of the notion that ARIP4 participates in the AR signaling pathway. Androgen-driven AR target genes include secreted proteins [kallikrein related peptidase 2 ( KLK2 ) and 3 ( KLK3 ); markers for prostate cancer screening and prognosis ( 30 , 31 )], proto-oncogenes { TMPRSS2 when fused with ERG ( 5 ) and growth factors [insulin-like growth factor 1 receptor ( 32 )]}, modulators of phosphatidylinositol 3-kinase (PI3K)/Akt and Notch signaling [ FKBP5 ( 33 ) and JAG1 ( 34 )], and transcription factors/tumor suppressors [NK3 Homeobox 1 ( NKX3.1 ) ( 35 , 36 ), ZBTB10 ( 37 ), and ZBTB16 ( 38 )]. Together, many AR target genes affected by loss of ARIP4 have been shown to promote prostate cancer growth, survival, and advancement ( 39 , 40 ), corroborating the important role of ARIP4 in conferring survival advantage (fig.…”