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Prostate cancer (PCa) continues to threaten men's health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554–65. ©2018 AACR.

AR expressions in various cell lines & combinational effects on PC3 and DU145

some data which support the conclusion in Figure 1, which further demonstrate the synergistic effect between two drugs.

IC50 of C4-2 cells

Figure legends of the supplementary figures

Quantification results of colony formation and Annexin V/PI staining

a negative control to show that synergistic effect does not exist in BRCA wildtype, p53 wildtype cells.

Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of the G1–S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA–mutant patient subgroups who might also respond favorably to PARPi. Mol Cancer Ther; 16(3); 469–79. ©2017 AACR.

The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival, and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here, we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin.Significance: This seminal report shows that activation of mTORC1 can be independent of AKT during mitosis. Cancer Res; 78(11); 2864–75. ©2018 AACR.

Cells expressing different forms of TSC1 (2A or 2E) have different mTORC1 activities

Figure S3 shows that Mre11 is not involved in normal mitosis.

The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment. Cancer Res; 77(12); 3169–80. ©2017 AACR.

Supplementary Materials and Methods and Figure legends

Supplemental methods and figure legends

The androgen receptor (AR) signaling pathway has been well demonstrated to play a crucial role in the development, progression, and drug resistance of prostate cancer. Although the current anti-androgen therapy could significantly benefit prostate cancer patients initially, the efficacy of the single drug usually lasts for a relatively short period, as drug resistance quickly emerges.We have performed an unbiased bioinformatics analysis using the RNA-seq results in 22Rv1 cells to identify the cell response toward Dip G treatment. The RNA-seq results were validated by qRT-PCR. Protein levels were detected by western blot or staining. Cell viability was measured by Aquabluer and colony formation assay.Here, we identified that Diptoindonesin G (Dip G), a natural extracted compound, could promote the proteasome degradation of AR and polo-like kinase 1 (PLK1) through modulating the activation of CHIP E3 ligase. Administration of Dip G has shown a profound efficiency in the suppression of AR and PLK1, not only in androgen-dependent LNCaP cells but also in castration-resistant and enzalutamide-resistant cells in a CHIP-dependent manner. Through co-targeting the AR signaling, Dip G robustly improved the efficacy of HSP90 inhibitors and enzalutamide in both human prostate cancer cells and in vivo xenograft mouse model.Our results revealed that Dip G-mediated AR degradation would be a promising and valuable therapeutic strategy in the clinic.

Retinitis pigmentosa and macular degeneration lead to photoreceptor death and loss of visual perception. Despite recent progress, restorative technologies for photoreceptor degeneration remain largely unavailable. Here, we describe a novel optogenetic visual prosthesis (FlexLED) based on a combination of a thin-film retinal display and optogenetic activation of retinal ganglion cells (RGCs). The FlexLED implant is a 30 µm thin, flexible, wireless µLED display with 8,192 pixels, each with an emission area of 66 µm2. The display is affixed to the retinal surface, and the electronics package is mounted under the conjunctiva in the form factor of a conventional glaucoma drainage implant. In a rabbit model of photoreceptor degeneration, optical stimulation of the retina using the FlexLED elicits activity in visual cortex. This technology is readily scalable to hundreds of thousands of pixels, providing a route towards an implantable optogenetic visual prosthesis capable of generating vision by stimulating RGCs at near-cellular resolution.

Increased abundance of polo-like kinase 1 (PLK1) is observed in various tumor types, particularly in lung adenocarcinoma (LUAD). Here, we found that PLK1 accelerated the progression of LUAD through a mechanism that was independent of its role in mediating mitotic cell division. Analysis of human tumor databases revealed that increased PLK1 abundance in LUAD correlated with mutations in KRAS and p53, with tumor stage, and with reduced survival in patients. In a mouse model of KRAS G12D -driven, p53-deficient LUAD, PLK1 overexpression increased tumor burden, decreased tumor cell differentiation, and reduced animal survival. PLK1 overexpression in cultured cells and mice indirectly increased the expression of the gene encoding the receptor tyrosine kinase RET by phosphorylating the transcription factor TTF-1. Signaling by RET and mutant KRAS in these tumors converged to activate the mitogen-activated protein kinase (MAPK) pathway. Pharmacological inhibition of the MAPK pathway kinase MEK combined with inhibition of either RET or PLK1 markedly suppressed tumor growth. Our findings show that PLK1 can amplify MAPK signaling and reveal a potential target for stemming progression in lung cancers with high PLK1 abundance.

Background: Bromodomain-containing protein 4 (BRD4) has been widely studied as an attractive therapeutic target of prostate cancer (PCa). Currently, a number of BRD4 inhibitors or degraders have been discovered. However, recent studies revealed that SPOP mutant of prostate cancer patients leads to BRD4 stabilization and resulted in JQ1-resistant. Therefore, to reveal the mechanism underlying BRD4 stability may improve the clinical response rate and efficacy of BRD4-targeted therapy in PCa patients. Methods: To evaluate the level of BRD4 during the mitosis phase, we applied a Confocal microscope and WB. In vitro kinase assay and Mass spectrometry were applied to test the phosphorylation of BRD4 by PLK1. A homemade phosphorylation-specific antibody was used to verify p-BRD4 in PCa cells and a tissue micro-array. A PDX-tumor model was used to evaluate the combination efficacy of Taxol to overcome JQ1-resistant. Result: We found that the level of BRD4 obviously decreased during the mitosis phase of PCa cells. Upon releasing from M-phase arrest, BRD4 level increased along with PLK1 decreasing in PCa cell lines, suggesting PLK1 might be involved in the degradation of BRD4 in the M-phase. We found that PBD domain of PLK1 was responsible for interacting with CTD of BRD4. Enforced overexpression of PLK1 promoted BRD4 dramatically reduced. Reversely, tet-induced depletion or inhibition of PLK1 led to BRD4 stabilization. Furthermore, applying gain or loss of function assay, we found that PLK1 directly phosphorylated BRD4 and triggered its phosphorylation-dependent degradation in M-phase, which was confirmed in clinical samples that high level of PLK1 was negatively correlated with BRD4. Accordingly, we found that overexpression of PLK1 lowered the stabilized BRD4 caused by SPOP mutant in PCa cells and consequently made cells sensitive to JQ1. Intriguingly, upon treated with Taxol, a commonly used medicine for PCa patients, PLK1 level was dramatically elevated as well as p-BRD4 status but total BRD4 downregulated in PCa cells. Moreover, sequential treatment of Taxol and JQ1 resulted in significant inhibition of proliferation, colony formation, and PDX tumor carrying SPOP mutant, indicating application of Taxol overcame JQ-1 resistant. Conclusion: Collectively, our results suggested that PLK1 phosphorylates BRD4 and consequently triggers its phosphorylation-dependent degradation in PCa cells. Sequential treatment of Taxol and JQ1 overcomes SPOP mutant-related BETi-resistant in prostate cancer. Citation Format: Yanquan Zhang, Ka Will Fong, Fengyi Mao, Ruixin Wang, Yifan Kong, Chaohao Li, Jinghui Liu, Zhiguo Li, Derek B. Allison, Dana Napier, Daheng Li, Jinpeng Liu, Chi Wang, Yeqing Zhang, Guangbing Li, Xiaoqi Liu. Taxol-elevated PLK1 overcomes BETi-resistant in prostate cancer via triggering phosphorylation-dependent degradation of BRD4. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4992.

Prostate cancer (PCa) is the most diagnosed worldwide. PCa development and progression require androgen receptor (AR) signaling, which stimulates its downstream gene expressions and cancer progression. While second-generation anti-androgen drugs plus androgen deprivation therapy (ADT) remains the first-line treatment for advanced prostate cancer patients, around one-third of patients will relapse in a short period. Advanced prostate cancer results in more mortalities than primary PCa patients. Evidence shows that the recurrence is caused by AR overexpression, AR variants, AR mutations, and signaling crosstalk. Thus, it is urgently needed to discover a novel therapeutic strategy for treating advanced prostate cancer. The heat shock protein family (HSP), including HSP90 and HSP70, play important roles in refolding aggregated protein for cancer cell proteomic equilibrium. HSP is induced primarily by heat shock factor (HSF1). As AR’s chaperone protein, HSP70 and HSP90 increase AR transcription activity. Inhibiting HSP70 and HSP90 promotes STUB1, an E3 ligase, binding to AR and AR - V7, and ubiquitination. Artesunate (ART) is a semi-synthetic ingredient from Artemisia annua and is the most common treatment for malaria throughout the world. It was approved for medical use by the FDA (Food and Drug Administration) (Food and Drug Administration). Recently ART has been unveiled for its anticancer properties. However, the efficacy of ART treatment in advanced prostate cancer and the direct target of ART have not been investigated yet. Herein, we have examined the efficacy of combining Enzalutamide (Enza) and ART in advanced prostate cancer cell lines. We also performed unbiased bioinformatics analysis using RNA seq results in enzalutamide-resistant cell line C4-2R cells and 22RV1 cells to investigate the cell response toward ART treatment. We identified ART could downregulate of AR signaling pathway. Moreover, we determined that ART treatment induces AR degradation in proteasome dependent manner. Interestingly, we found HSP70 and HSP90 are also decreased in RNA seq results. Taking these together suggests that ART may target HSF1 directly. Our results suggest ART induced AR degradation could be a promising clinical strategy for advanced prostate cancer. Citation Format: Xinyi Wang, Fengyi Mao, Jinghui Liu, Yifan Kong, Dang he, Chi Wang, Zhiguo Li, Xiaoqi Liu. Artesunate increases enzalutamide efficacy in advanced prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5508.

Polo-like kinase 1 (Plk1) has been reported to be highly expressed in most tumors, especially in advanced tumors, while how Plk1 elevation benefits tumor growth remains elusive. Metabolic reprogramming is one of the hallmarks of cancer, but how the tumors fully take advantage of deregulated metabolism is an enigma. Here, we found that Plk1 could divert serine metabolism from de novo synthesis to exogenous uptake by regulating PHGDH (phosphoglycerate dehydrogenase), the first rate-limiting enzyme of de novo serine biosynthesis. We show that PHGDH is phosphorylated by Plk1 at a cluster site (S512, S513, S517) and that Plk1-associated phosphorylation of PHGDH results in its protein degradation, thus reduced de novo serine biosynthesis. As a compensatory response, cells with an elevated level of Plk1 significantly increase the uptake of serine to produce more sphingosines, which are pivotal metabolites for the growth of cancer cells. Our finding may provide guidance on how to target de novo biosynthesis of serine, serine uptake or sphingosine metabolism to treat advanced prostate cancer. Citation Format: Xiongjian Rao, Derek B. Allison, Robert M. Flight, Yuanyuan Wu, Timothy Scott, Daheng He, RuiXing Wang, Zhiguo Li, Chaohao Li, Yifan Kong, Fengyi Mao, Chi Wang, Richard M. Higashi, Andrew N. Lane, Hunter NB Moseley, Xiaoqi Liu. Plk1 phosphorylation of PHGDH to regulate serine metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3673.

Non-small cell lung cancer (NSCLC) is one of the most aggressive cancer types, and metastasis of cancer cells is the major reason leading to death of patients. Aryl hydrocarbon receptor (AHR) is an important transcription factor involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, is another oncogene that promotes the malignancy of multiple cancer types. Preliminary examination indicates that AHR is a potential substrate of PLK1. Nonetheless, the phosphorylation and interaction of these two factors, as well as the subsequent biological significance in lung cancer remain to be determined. Here we prove that PLK1 phosphorylates AHR at serine 489 (S489) in lung adenocarcinoma (LUAD), a subtype of NSCLC. Overexpressing of exogenous AHR with mutation of phosphomemetic amino acid (S489D), enhances migration and invasion in transwell assays compared to cells harboring AHR that is unable to be phosphorylated (S489A), indicating that phosphorylation of AHR by PLK1 induces the metastatic potential of lung cancer. This is further confirmed in mouse studies using intravenous or subcutaneous inoculation of cancer cells. RNA-seq analyses of cells with S489D or S489A show that type 2 deiodinase (DIO2) is underrepresented in S489A but overexpressed in S489D. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which is the more active form of thyroid hormone and activates downstream effect. Treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or treatment with deiodinase inhibitor iopanoic acid disrupts this property. Furthermore, this phenomenon is verified by in vivo mouse experiment using intravenous injection of DIO2-depleted cancer cells. Taken together, these results identify phosphorylation of AHR by PLK1 as a mechanism that leads to progression of LUAD. Citation Format: Chaohao Li, Daheng He, Fengyi Mao, Xinyi Wang, Yanning Hao, Yifan Kong, Christine F. Brainson, Jinghui Liu, Yanquan Zhang, Ruixin Wang, Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Sai Wu, Chi Wang, Qiou Wei, Jianlin Wang, Xiaoqi Liu. Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via upregulation of DIO2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2578.

Hexavalent chromium (Cr(VI)), an class I environmental carcinogen, not only induces lung epithelial cell transformation but also promotes lung cancer progression by alterations of the cell cycle and cellular energy metabolism. Using Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and parental BEAS-2B cells, we demonstrate that the level of polo-like kinase 1 (PLK1) is highly upregulated in CrT cells, which blocks mitochondrial function, and further promotes cell proliferation both in vitro and in vivo. Cells expressing a high level of PLK1 exhibited repressed mitochondrial activity due to defective modulation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), which facilitates the carbon influx to TCA cycle via catalyzing pyruvate/Acetyl-CoA conversion. Mechanistically, we show that PDHA1 can be directly phosphorylated by PLK1 at T57, which triggers collapse of E1 and PDHA1 degradation via activation of mitophagy. These defects resulted in the inhibition of oxidative phosphorylation and reduction of mitochondrial reactive oxygen species (ROS) generation, eventually inhibiting mitochondrial-mediated apoptotic response. Defining the role of PLK1 in metabolic reprogramming in Cr(VI)-associated cancer progression may give us a new perspective and a target to inhibit Cr(VI)-induced cancer development. In addition, PLK1 inhibitors may be used to increase the chemo-sensitivity of cancer cells by restoring the normal function of mitochondria, thus alleviating the drug resistance caused by dysfunction and hyperpolarization of mitochondria. Citation Format: Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Derek B. Allison, Qi Qiao, Zhuangzhuang Zhang, Yifan Kong, Ruixin Wang, Teresa W. Fan, Richard M. Higashi, Andrew N. Lane, Xiaoqi Liu. Dysregulation of mitochondrial function by PLK1-mediated PDHA1 phosphorylation promotes Cr(VI)-associated lung cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4840.

Melanoma is one of the most frequently diagnosed cancers in the caucasian population of both genders. The survival rate of advanced melanoma patients will be exceedingly poor, as low as 27.3%. BRAF-V600E is the most common mutation found clinically, resulting in the constitutive activation of the MAPK signaling pathway. Vemurafenib, a specific inhibitor of mutant BRAF, has shown an impressive response in phase 3 clinical trials and was approved by FDA in 2011. However, due to the rapid development of resistance, the duration of response under a single treatment is frequently short, highlighting the urgent requirement for novel therapy in melanoma treatment. Polo-like kinase 1 (PLK1), a crucial cell cycle regulator, participates in multiple mitotic processes, including centrosome maturation, mitotic entry, spindle assembly, sister chromatid segregation, mitotic exit, and cytokinesis. Compared to normal tissues, the expression level of PLK1 significantly upregulates in multiple cancers. More importantly, the expression level of PLK1 negatively correlates with the melanoma patients’ survival rate based on the TCGA database. Besides, PLK1 is identified as an oncogene to promote proliferation, motility, and resistance to various drugs. In the present study, we found that overexpression of PLK1 promotes tumor growth, metastasis, metabolic reprogramming, and vemurafenib resistance in the BrafCA/Ptenloxp mouse melanoma model. Through phosphorylation, overexpressed PLK1 stabilizes BACH1, a critical transcriptional factor of multiple metastatic and metabolic genes, and protects it from degradation. Subsequently, a higher level of BACH1 leads to increasing metastasis, upregulation of glycolysis, and suppression of OXPHOs. Besides, we have validated the strong synergy between PLK1 inhibitor volasertib and vemurafenib in treating melanoma carrying BRAF-V600E. Our in vitro and in vivo experiments have shown an improved efficacy of this combined therapy on inhibition of cell proliferation, induction of cell death, and suppression of cell metastasis compared to mono-treatment. In short, our data has indicated PLK1 as a potent and promising target in cancer treatment. Citation Format: Fengyi Mao, Yifan Kong, Chaohao Li, Yanquan Zhang, Xiongjian Rao, Qiongsi Zhang, Xinyi Wang, Zhiguo Li, Xiaoqi Liu. PLK1 promotes the metastasis and drug resistance in melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4997.

As an emerging route to further lower the production cost, reducing the thickness of Cu(In,Ga)Se2 (CIGS) absorber has drawn substantial attention and has been intensively studied in recent years. H...

Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer, including prostate cancer (PCa), is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers, including PCa. This suggests that cutting off the secretion or expression of PD-L1 might improve the response rate of PD-L1 blockade therapy in PCa treatment. Here we report that p300/CBP inhibition by a small molecule p300/CBP inhibitor dramatically enhanced the efficacy of PD-L1 blockade treatment in a syngeneic model of PCa by blocking both the intrinsic and interferon gamma (IFN-γ)-induced PD-L1 expression. Mechanistically, p300/CBP could be recruited to the promoter of CD274 (encoding PD-L1) by the transcription factor IRF-1, which induced the acetylation of Histone H3 at CD274 promoter followed by the transcription of CD274. A485, a p300/CBP inhibitor, abrogated this process and cut off the secretion of exosomal PD-L1 by blocking the transcription of CD274, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. This finding reports a new mechanism of how cancer cells regulate PD-L1 expression through epigenetic factors and provides a novel therapeutic approach to enhance the efficacy of immune checkpoint inhibitors treatment.

It is well-established knowledge that the formation of a V-shape Ga double grading along the thickness direction of a Cu(In,Ga)Se2 (CIGS) absorber is beneficial and critical for highly efficient CIGS thin film solar cells. However, when the thickness of the absorber is reduced from the normal value to a submicron level value, the formation of such a Ga double grading becomes very difficult due to rapid element inter-diffusion. In this work, a novel growth route that introduces a pre-deposited CuGaSe2 (CGS) layer at the beginning of the traditional three-stage co-evaporation method is developed to successfully form the Ga double grading in submicron CIGS. It has been demonstrated that the pre-deposited CGS layer can not only result in the formation of a steep Ga back grading but also improve the performance of the submicron CIGS solar cells. As a result, a submicron CIGS solar cell with over 15% conversion efficiency without anti-reflective coating (ARC) has been obtained after a suitable Ga double grading was created in the submicron thick absorber.