A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma

Abstract

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

MBOAT7-Driven Phosphatidylinositol Remodeling Promotes the Progression of Clear Cell Renal Carcinoma

“…Similar to other solid tumors, ccRCC is primarily driven by loss of key tumor suppressor such as von Hippel-Lindau (VHL) and activation of oncogenes (23)(24)(25). Closely associated with these genetic alterations, lipid metabolic processes are dramatically altered in the ccRCC tumor microenvironment (3,4,(26)(27)(28)(29)(30)(31)(32)(33). In fact, the "clear cell" subtype gets its name from cholesterol ester-rich lipid droplets that accumulate in tumor cells (32,33).…”

Kruppel‐like factor 6 promotes macrophage inflammatory and hypoxia response

“…Alterations in KLF6 expression or function has been associated with the pathogenesis of numerous human ailments, including inflammatory bowel diseases, cancer, hepatic steatosis, and hepatic fibrosis . A recent study by Syafruddin et al demonstrated that HIF2α directly elevates KLF6 expression to promote SREBF1/SREBF2‐dependent lipid metabolism, growth and survival of clear cell renal cell carcinomas . Studies from our laboratory have uncovered that KLF6 is predominantly expressed in cells of myeloid origin and KLF6 deficiency significantly attenuated inducible pro‐inflammatory gene expression in macrophages .…”

“…15 A recent study by Syafruddin et al demonstrated that HIF2α directly elevates KLF6 expression to promote SREBF1/SREBF2-dependent lipid metabolism, growth and survival of clear cell renal cell carcinomas. 18 Studies from our laboratory have uncovered that KLF6 is predominantly expressed in cells of myeloid origin and KLF6 deficiency significantly attenuated inducible pro-inflammatory gene expression in macrophages. 19 At the molecular level, KLF6 robustly elevate pro-inflammatory gene expression by promoting NFκB functions as well as repressing critical anti-inflammatory genes such as PPARγ, BCL6, and miR-223 expression in macrophages.…”

The role of KLF14 in multiple disease processes

“…Multiple studies have indicated that KLFs are involved in the many different physiological and pathological processes. In recent studies, KFLs have been reported to play a critical role in the maintenance of homeostasis of many critical systems, including cardiovascular, cerebral, renal, immune, digestive, respiratory, and hematopoietic system . For example, in hepatobiliary system, KLF2 and KLF11 are shown to play roles in the hepatic fibrogenesis.…”

“…In recent studies, KFLs have been reported to play a critical role in the maintenance of homeostasis of many critical systems, including cardiovascular, cerebral, renal, immune, digestive, respiratory, and hematopoietic system. [2][3][4][5][6][7][8] For example, in hepatobiliary system, KLF2 and KLF11 are shown to play roles in the hepatic fibrogenesis. KLF4, KLF6, KLF8, KLF9, and KLF17 are shown to be involved in the pathogenesis of hepatocellular carcinoma (HCC) by modulating the invasion, proliferation, apoptosis, and migration of the cancer cells.…”