Krüppel-like Factor 10 for Prognostic and Predictive Biomarker: History
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Contributor:
Yi-Chih Tsai
,
Min-Chieh Hsin
,
Rui-Jun Liu
,
Ting-Wei Li
,
Hui-Ju Ch’ang

Despite recent improvement in chemotherapy regimens for pancreatic adenocarcinoma (PDAC), the clinical outcomes are still unsatisfactory compared to other solid tumors. Radiotherapy was demonstrated to improve locoregional control of PDAC; however, the survival benefit of radiotherapy in localized PDAC is undefined due to early distant progression in the majority of patients. Upfront chemotherapy for localized PDAC was suggested recently to avoid radical local therapy for patients of localized PDAC high risk of distant metastasis. Potential tissue biomarkers were developed to select PDAC patients who will benefit from local radiotherapy. 

  • pancreatic adenocarcinoma
  • radiotherapy
  • tissue biomarker

1. KLFs

KLFs are of the specificity protein 1 (SP1)-like/KLF transcription factor superfamily and are characterized by the absence of a Buttonhead box, namely CXCPXC [1]. The DNA-binding domain of KLFs, located at the carboxyl terminus, contains three conserved C2H2 zinc finger structures. It enables KLFs to recognize CACCC elements or GC-boxes and to bind to regulatory regions of the target genes [2]. Eighteen unique members of the KLF family were identified, with a >65% sequence similarity for zinc finger motifs, resulting in competition for binding to promoters of target genes. Group 1 consists of KLF3, KLF8, and KLF12 which behave as transcriptional repressors by interacting with proteins binding to the carboxyl terminus. Group 2 includes KLF1, KLF2, KLF4, KLF5, KLF6, and KLF7 which bind to acetyltransferases and function as transcriptional activators. Group 3 comprises KLF9, KLF10, KLF11, KLF13, KLF14, and KLF16 which are transcriptional repressors and interact with switch-independent-3 family member A (Sin3A), a common transcriptional corepressor. Nowadays, KLF15, KLF17, and KLF18 remain unclassified [3]. KLFs are known to be critical regulators of many important biological processes, such as cell proliferation, differentiation, survival, cell cycle, epithelial–mesenchymal transition (EMT), invasion, metastasis, cell maturation, and organogenesis. Dysregulation of KLF function can lead to the development of cancer and other disorders [4].

2. KLF10

KLF10 was identified in human fetal osteoblasts as a positive regulator of bone growth [5]. The protein homology of KLF10 among humans, Mus musculus, Bos taurus, and Liacerta agilis is as high as 81.28%, suggesting its critical role in biological processes [6]. KLF10 is an early-response mediator of TGFβ/SMAD signaling. It forms a positive feedback loop with TGF-β signaling by transcriptionally regulating SMAD2 and SMAD7 [7]. Estrogen stimulates KLF10 expression, which inhibits BAX inhibitor-1 transcription and enhances breast cancer cell apoptosis [8]. Jun B and lysine demethylase 6A may facilitate KLF10 transcription to exacerbate diabetic nephropathy [9]. Multiple long noncoding RNAs (lncRNA) and microRNAs (miRNA) were identified as upstream regulators of KLFs, thus providing essential pathways for targeting KLFs. E3 ubiquitin ligases, including seven in absentia homolog-1 (SIAH1) and FBW7, interact with KLF10 through conserved binding motifs to promote the proteasomal degradation of KLF10. The binding of KLF10 to itchy E3 ubiquitin ligase (ITCH) increases KLF10 levels and activates Foxp3 transcription in regulatory T cells [10][11].

3. Involvement of KFL10 in Multiple Diseases

KLF10 is involved in glucose and lipid metabolism, mitochondrial structure and function, cell proliferation, and apoptosis and it plays critical roles in multiple diseases [12]. It is a clock-controlled gene that maintains the hepatic circadian rhythm which is essential for regulating hepatic glucose and lipid homeostasis [6]. Sex-dependent differences were found in the metabolic phenotypes of KLF10-knockout mice. Male mice exhibited post-prandial and fasting hyperglycaemia whereas female mice exhibited increased plasma triglyceride levels. As a circadian-clock-controlled transcription factor, KLF10 suppresses lipogenic genes of glucose and lipid metabolism in the liver and it affects gluconeogenesis, contributing to diabetes [13][14]. KLF10 alleviates hepatic steatosis and nonalcoholic-steatohepatitis by downregulating SREBP-1c involving lipogenesis [15][16]. KLF10-deficient mice exhibit reduced receptor activator of nuclear factor kappa-B ligand, increased osteoprotegerin, and delayed8 osteoclast differentiation which led to reduced bone turnover and osteopenia [12][14][17]. A study reported that male KLF-knockout mice developed cardiac hypertrophy after approximately 16 months due to the angiotensin II-induced cardiac transcription factor, GATA4, and the atrial natriuretic factor, brain natriuretic peptide [18]. KLF10 can transactivate Foxp3 promoters in regulatory T cells in response to TG-β1 to promote atherosclerosis [19][20].

4. KLF10 in Cancer

Many studies have demonstrated the tumor suppressor function of KLF10 in terms of cell proliferation inhibition and apoptosis induction [21][22]. KLF10 loss activates PTEN/PI3K/AKT activity in multiple myeloma and bladder cancer [23][24]. KLF10 overexpression can suppress Wnt signaling and GSK3β phosphorylation to inhibit the proliferation, migration, and drug resistance of multiple myeloma cells. Knock-down of securin, the downstream target of KLF10, can mimic the tumor suppressor role of KLF10 in multiple myeloma [25]. In advanced-stage cancer, TGF-β signaling enhances the EMT whereas KLF10 inhibits TGF-β-induced EMT. KLF10 can suppress lung and pancreatic cancer EMT and invasion by recruiting HDAC1 to suppress the SNAI2 promoter for the removal of histone acetylation (H3K9ac and H3K27ac) [26]. In oral squamous cell carcinoma, KLF10 was identified as a differentially expressed circadian-related gene that was correlated with OS (p < 0.05) and the drug response (p = 0.0014) [27]. By directly binding to the LINC00629 promoter to induce Mcl1 degradation, KLF10 exerts antitumor activity in oral squamous cell carcinoma treated with apigenin, a flavonoid [28]. KLF10 is involved in cervical cancer immunoediting by transcriptionally regulating IL6, IL25, and pregnancy-specific beta-1 glycoproteins 2 and 5 [29]. Conversely, the tumor suppressive role of KLF10 may vary depending on the tumor cells types and the microenvironments. In KLF10-knockout mice, the TGF-β-SMAD signaling pathway was activated to suppress diethylnitrosamine-induced hepatocyte proliferation in the liver cancer [30].

5. Role of KLF10 in PDAC Progression

Studies have revealed associations between PDAC and alterations in TGF-β receptor genes and SMAD [31][32]. However, no alterations in KLF10 expression were found in a mutation screening study of 22 human pancreatic cancer cell lines [33]. KLF10 expression in various cancer tissues has been reported to be significantly lower than that in normal tissues [26][34]. In PDAC, KLF10 expression was low in two thirds of patients and was inversely correlated with the cancer stage [16][35]. Despite alterations in the TGF-β signaling pathway components in patients with PDAC, KLF 10 could regulate TGF-β signaling and inhibit epithelial cell proliferation in pancreatic cancer cells [36]. KLF10 expression can be increased by a noncoding RNA, lncRNA FLVCR1-AS1, by acting as a competitive endogenous RNA to sequester the inhibitory effects of miR-513c-5p or miR-514b-5p. Since lncRNA FLVCR1-AS1 is a direct transcriptional target of KLF10, this FLVCR1-AS1/KLF10 positive feedback loop can suppress PDAC progression [37].
In the murine model of pancreas-specific KLF10 deletion (Pdx-1Cre KLF10L/L), no evidence of abnormal pancreas development or neoplastic lesions was noted. The synergistic effects of KLF10 inactivation-activated mutant KrasG12D in cross-breed mice led to the rapid onset of advanced PDAC with 50% penetrance. The upregulation of c-Jun and SDF-1/CXCR4 signaling after KLF10 deletion was responsible for accelerated PDAC cell growth and distant metastasis [38]. Since KLF10-knockout mice exhibited a high incidence of metabolic disorders, researchers previously explored sirtuin6, an NAD+-dependent deacetylase downstream of KLF10, as a key regulator of glucose homeostasis and a tumor suppressor. The  findings indicated that KLF10 transcriptionally activated sirtuin6 to modulate the EMT and glycolysis of PDAC coordinately through NFκB and HIF1α [39]. In addition to the Wnt/β-catenin signaling pathway, researchers demonstrated that KLF10 contributed to the cancer stemness phenotype by transcriptionally regulating Notch-3 and Notch-4 and competing with E74-like ETS transcription factor 3 (ELF3) for promoter binding. A combination of metformin, which upregulates KLF10 by phosphorylating AMP-activated protein kinase, and evodiamine, a nontoxic Notch-3 methylation stimulator, ameliorated PDAC growth through KLF10 downregulation [40].

6. Role of KLF10 in PDAC Resistance to Radiotherapy

The KLF family regulate radiosensitivity in various cancers. KLF2 and KLF4 are positive regulators of endothelial-protective molecules such as nitric oxide and thrombomodulin. Compared with single-dose radiation, fractionated radiation markedly reduced the ERK5/KLF2 pathway and enhanced ICAM-1 expression, leading to endothelial dysfunction [41]. KLF4 and KLF5 may prevent radiation-induced intestinal injury by inhibiting apoptosis and modulating DNA repair pathways [42][43]. KLF4 expression can predict radiotherapy resistance and poor clinical outcomes for cervical cancer. From tumor tissues of 117 patients with locally advanced cervical cancer, KLF4 was disclosed as a risk factor for radioresistance (p = 0.032), poor PFS (p = 0.001), and OS (p < 0.001) [44]. KLF5 was the predictor of poor response to CRT in rectal cancer [45]. In colon cancer cells, radiation time-dependently and dose-dependently stabilized KLF5 levels. KLF5 increased cyclin D1 and β-catenin levels to mediate cell survival. A study assessing 60 colorectal tumor tissues before radiotherapy indicated that high KLF5 expression was correlated with pathologic complete remission (p = 0.023) and radioresistance in colorectal cancer [45]. High KLF6 expression level was associated with a nearly four times higher risk of local recurrence in head and neck cancer patients after radiotherapy (p = 0.008) [46].
KLF10 gene expression can be used to discriminate between γ-radiation and α-radiation quality [47]. Radiation-induced delayed neuropsychiatric disorders was associated with biological processes, such as protein kinase activity, circadian behavior, and cell differentiation. The alteration of expression levels of six genes, including KLF10, in the chronic phase of radiation increased anxiety-like behaviors in mice [48]. Radiation-induced KLF10 upregulation was noted in many cancer cell lines and murine models [47][48][49]. KLF10 transcriptionally downregulated EGFR and modulated gemcitabine-resistance in cholangiocarcinoma [50]. In esophageal squamous cell carcinoma, exosomes secreted from hypoxic tumors after radiation expressed high levels of miR-340-5p, which suppressed KLF10 transcription. Higher miR-340-5p expression and lower KLF10 expression in plasma exosomes from patients with esophageal cancer patients were associated with poorer radiation responses and prognosis [51]. Several studies, including ours, have demonstrated that KLF10 transcriptionally suppresses the UV radiation resistance-associated gene (UVRAG) and modulates apoptosis, DNA repair, and autophagy in cancer cells. Metformin might decrease radioresistance in pancreatic and esophageal cancers by elevating KLF10 expression [51][52]. Furthermore, EMT and cancer stem cell phenotypes also contribute to radioresistance [53][54]. KLF10 modulates EMT and can lead to cancer stemness phenotypes by transcriptionally regulating sirtuin6, Notch-3, and Notch-4, respectively, and thus may cause radioresistance in PDAC [38][39][40]. Whether KLF family members share promoter binding sites on UVRAG or other signal targets and regulate the balance between radiosensitivity and radioresistance warrants further exploration.

7. Selection of Patients with Resectable PDAC for Radiotherapy Using KLF10 and SMAD4

To evaluate the benefits of additional CRT to standard adjuvant chemotherapy in patients with resected PDAC, researchers conducted a randomized clinical trial from 2009 to 2015 [55]. Researchers enrolled 147 patients with PDAC after curative resection and randomized them to either adjuvant GEM 1000 mg/m2 infusion weekly for six cycles or adjuvant GEM for three cycles and GEM (400 mg/m2 weekly)-based CRT and another three cycles of GEM. Despite the significant locoregional benefit (p = 0.039) of additional CRT, the median recurrence-free survival and OS were of no significant difference in the two arms (HR: 0.98, p = 0.89 and HR: 1.04, p = 0.82), respectively [55]. Tumor specimens were collected from 111 patients. Immunohistochemical expression of biomarkers including KLF10, SMAD4, and RUNX3 was evaluated by pathologists using a visual grading system based on staining intensity and extent. The postoperative CA19-9 level and protein expression of KLF10 and SAMD4, were significantly associated with OS (p = 0.047, 0.013, and 0.045, respectively). High KLF10 or SMAD4 expression in patients (n = 55) receiving additional adjuvant CRT had a significantly prolonged local control time (ꚙ vs. 19.8 months, p = 0.026) and a better OS (33.0 vs. 23.0 months, p = 0.12) than those receiving GEM alone. In resected PDAC patients who had a loss of both SMAD4 and KLF10, additional adjuvant CRT caused the rapid development of distant metastasis and worse clinical outcomes [56]. The combination of KLF10 and CA19-9 levels did not reveal significant differences in survival outcomes between the treatment arms [56]. On the basis of these findings, researchers  concluded that the chances of translating locoregional control of CRT into prolonged survival were high in patients with KLF10- or SMAD4-expressing tumors. Although these findings are promising, a prospective study is warranted to validate the results.

This entry is adapted from the peer-reviewed paper 10.3390/cancers15215212

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